After graduating from the University of Zurich in 1957, Kübler-Ross moved to New York in 1958 to work and continue her studies.

She commenced her psychiatric residency in the Manhattan State Hospital on July 6, 1959, marking the beginning of her career working by creating her own treatments for those who were schizophrenic along with those faced with the title "hopeless patient", a term used at the time to reference terminal patients. These treatment programs would work to restore the patient's sense of dignity and self-respect. Kübler-Ross also intended to reduce the medications that kept these patients overly sedated, and found ways to help them relate to the outside world. During this time, Ross was horrified by the neglect and abuse of psychiatric patients as well as the imminently dying. She found that the patients were often treated with little care or completely ignored by the hospital staff. This realization made her strive to make a difference in the lives of these individuals. She developed a program that focused on the individual care and attention for each patient. This program worked incredibly well, and resulted in significant improvement in the mental health of 94% of her patients.

In 1962, she accepted a position at the University of Colorado School of Medicine. There, Kübler-Ross worked as a junior faculty member and gave her first interview of a young terminally ill woman in front of a roomful of medical students. Her intentions were not to be an example of pathology, but she wanted to depict a human being who desired to be understood as she was coping with her illness and how it has impacted her life. She stated to her students:

"Now you are reacting like human beings instead of scientists. Maybe now you'll not only know how a dying patient feels but you will also be able to treat them with compassion – the same compassion that you would want for yourself."

Kübler-Ross completed her training in psychiatry in 1963, and moved to Chicago in 1965. She sometimes questioned the practices of traditional psychiatry that she observed. She also undertook 39 months of classical psychoanalysis training in Chicago. She became an instructor at the University of Chicago's Pritzker School of Medicine, where she began to conduct a regular weekly educational seminar consisting of live interviews with terminally ill patients. She had her students participate in these despite a large amount of resistance from the medical staff.

By 1966, Kübler-Ross was giving regular weekly seminars on dying patients at her hospital. In late 1966, she wrote a seventeen-page article titled "The Dying Patient as Teacher: An Experiment and an Experience" for the December issue of The Chicago Theological Seminary Journal, which was themed "On Death and Dying." Although she expressed concerns about her English proficiency, the editor reassured her. Despite the journal's limited circulation, a copy of her article reached an editor at Macmillan Publishing Company in New York City. Consequently, on July 7, 1967, Macmillan offered Kübler-Ross a contract to expand her work into a 256-page book titled "On Death & Dying." Coincidentally, just six days later, on July 13, 1967, St. Christopher's Hospice, the first modern hospice, admitted its inaugural patient. The book was officially registered with the US copyright office on May 19, 1969. Despite delays, the book was eventually published in November 1969 and quickly became a best-seller, profoundly altering her life. Notably, as of December 18, 1976, "On Death & Dying" remained on the New York Times Best Seller list for trade paperbacks, listing at #3.

In November 1969, Life magazine ran an article on Kübler-Ross, bringing public awareness to her work outside of the medical community. The response was enormous and influenced Kübler-Ross's decision to focus her career on working with the terminally ill and their families. The intense scrutiny her work received also had an impact on her career path. Kübler-Ross stopped teaching at the university to work privately on what she called the "greatest mystery in science"—death.

During the 1970's, Kübler-Ross became a champion of the worldwide hospice movement. She traveled to over twenty countries on six continents initiating various hospice and palliative care programs. In 1970, Kübler-Ross spoke at the prestigious Ingersoll Lecture at Harvard University on the subject of death and dying. On August 7, 1972, she spoke to the United States Senate Special Committee on Aging to promote the "Death With Dignity" movement. In 1977, she was named "Woman of the Year" by Ladies' Home Journal. In 1978, Kübler-Ross cofounded the American Holistic Medical Association.

Kübler-Ross was one of the central figures in the hospice care movement, believing that euthanasia prevents people from completing their "unfinished business".

In 1977, she founded "Shanti Nilaya" (Home of Peace) on forty acres of land in Escondido, California. At this time, Kübler-Ross began conducting "Life, Death, and Transition (LTD) workshops with the goal of assisting people to resolve their "unfinished business", using Shanti Nilaya as a setting for some of these five-day workshops. She also intended it as a healing center for the dying and their families. She was also a co-founder of the American Holistic Medical Association during this time period.

In the late 1970s, after interviewing thousands of patients who had died and been resuscitated, she became interested in out-of-body experiences, mediumship, spiritualism, and other ways of attempting to contact the dead. This led to a scandal connected to the Shanti Nilaya Healing Center, in which she was duped by Jay Barham, founder of the Church of the Facet of the Divinity. Claiming he could channel the spirits of the departed and summon ethereal "entities", he encouraged church members to engage in sexual relations with the "spirits". He may have hired several women to play the parts of female spirits for this purpose. Kubler-Ross' friend Deanna Edwards was invited to attend a service to ascertain whether allegations against Barham were true. He was found to be naked and wearing only a turban when Edwards unexpectedly pulled masking tape off the light switch and flipped on the light. Despite the accusation of sexual misconduct Kübler-Ross defended him for over a year. The authorities did not press charges against the Barhams. Then she announced the ending of her association with both Jay Barham and his wife Martha in her Shanti Nilaya Newsletter (issue 7) on June 7, 1981.

Kübler-Ross also dealt with the phenomenon of near-death experience. She was also an advocate for spiritual guides and afterlife, serving on the Advisory Board of the International Association for Near-Death Studies (IANDS). Kübler-Ross reported her interviews with the dying for the first time in her book, On Death and Dying: What the Dying Have to Teach Doctors, Nurses, Clergy, and Their Own Families (1969). Originally, this book had a thirteenth chapter on near-death experiences but her colleagues strongly advised her to remove it for the sake of public acceptance, which she did before the book went to press.

In 1981, she appeared on an Australian radio documentary about death and near-death experiences that aired on the ABC, And When I Die, Will I Be Dead? It was adapted into a book in 1987.

Kübler-Ross went on to write several books about near-death experiences (NDEs). Her book On Life After Death (1991) was compiled from three lectures she gave:

"Leben und Sterben" (Living and Dying), a speech she made in Switzerland in December 1982 in the German language.
"There is no Death", given in San Diego in 1977.
"Life, Death, and Life After Death", a recorded lecture she gave in 1980.
The English language edition sold over 200,000 copies. The German Language edition also was a best seller with 100,000's sold.

Another book, The Tunnel and The Light (1999), originally entitled Death is of Vital Importance, was also composed of various lectures she had previously given.

In the late 1970s, Kübler-Ross developed a series of 5-day residential workshops aimed at helping individuals who were nearing the end of their lives to live more fully during their remaining time. These workshops were designed to accommodate not only the dying but also their caregivers, who were encouraged to participate in the sessions. The workshops provided a forum for patients to share their stories and express their fears, anger, and grief regarding their impending death. A recurring theme in the workshops was addressing regrets associated with perceived wasted time and energy related to unresolved childhood issues such as abuse and neglect. These unresolved issues often manifested as misplaced anger, perfectionism, controlling behavior, prioritization of material wealth over relationships, feelings of unworthiness, and a lack of meaning.

To address the intensity of these emotions, Dr. Kübler-Ross incorporated techniques to help participants externalize their emotions, including the release of buried rage, grief, and fear. This approach often facilitated a deeper understanding and resolution of long-standing pain, leading to a transformation of fear and grief into gratitude. Recognizing that caregivers also benefited from the workshops, Dr. Kübler-Ross opened the sessions to anyone seeking to live more fully until death.

A distinctive feature of the workshops was the use of impromptu crayon drawings, a technique influenced by the work of Jungian analyst Dr. Susan Bach. Dr. Kübler-Ross instructed participants on drawing interpretation to help uncover unconscious reasons for their attendance and to address past losses. Additionally, she presented a model of human development encompassing four parts— emotional, intellectual, physical, and spiritual—referred to as "The Four Quadrants," which forms the basis of her work in the beginnings of the palliative care movement. She also addressed what she called "the five core emotions" —fear, anger, natural jealousy, grief, and love—and their natural expressions and distortions.

Throughout her career, Kübler-Ross extensively studied and wrote about children's perceptions of death. Her notable works include The Dougy Letter (1979), Living with Death and Dying (1981), and On Children and Dying (1983). These books explore how children understand, discuss, and respond to death, reflecting her insights into the unique ways children express their experiences and fears. Kübler-Ross's work was partly driven by requests from patients and readers seeking a deeper understanding of the language used by terminally ill children to articulate their needs. In Living with Death and Dying (1981), she argues that children have a more nuanced awareness of death than often assumed and are more willing to discuss it openly. Influenced by the work of Susan Bach and Gregg Furth, Kübler-Ross examined how children's drawings serve as a crucial means of communication. She identified two distinct types of communication related to death in children. "Nonverbal Symbolic Language" is used by younger children, who may express their understanding of death through drawings, pictures, or objects, as they might lack the verbal skills to articulate their feelings directly. As children grow older, they may transition to "Verbal Symbolic Language," characterized by complex stories and unusual questions that serve to express their emotions and concerns about death. Children may be fearful of asking direct questions regarding their death, so they may come up with stories or strange questions that will meet their needs. This form of communication reflects their evolving ability to articulate their feelings and fears, though they may still struggle with direct inquiries about death.

During a time when patients suffering from AIDS were being disowned and discriminated against for their illness, Kübler-Ross accepted them with open arms. She conducted many workshops on life, death, grief, and AIDS in different parts of the world, teaching about the disease and working to reduce the stigma surrounding it. Later, she created a workshop meant solely for patients who had contracted AIDS; even though the majority of people who contracted AIDS at that time were gay men, women and children also contracted the disease. This surprised her, as she had not expected just how many children and babies had contracted the terminal illness. She noted in her book that babies typically contracted the disease through the mother or father or through contaminated blood transfusions, also remarking that older children that had the disease may have contracted it due to sexual assault from someone who was HIV-seropositive.

During this period, Kübler-Ross became developed an interest in the concept of prison hospice care. In the mid-1980's, the prison facility at Vacaville, California emerged as the primary site for delivering healthcare services to incarcerated individuals. In 1984, Kübler-Ross delegated one of her staff members, Irene Smith to conduct an investigative assessment of conditions at this institution. Subsequently, Kübler-Ross enlisted the aid of Nancy Jaicks Alexander, a workshop leader in Kübler-Ross' Life, Death, and Transition (LDT) workshops, to further explore avenues for enhancing end-of-life care for AIDS patients confined at the Vacaville facility. Nancy alongside her husband, Robert went on to co-found the first prison hospice in 1992. Concurrently, Kübler-Ross pursued additional prison-related initiatives in Hawaii, Ireland and Scotland throughout the 1980s. In June 1991, she held her first LDT workshop inside a prison at Edinburgh's Saughton Prison (HM Prison). One of her greatest wishes was to build a hospice for abandoned infants and children infected with HIV to give them a lasting home where they could live until their death. Kübler-Ross attempted to set this up in the late 1980s in Virginia, but local residents feared the possibility of infection and blocked the necessary re-zoning. In October 1994, she lost her house and many possessions, including photos, journals, and notes, to an arson fire that is suspected to have been set by opponents of her AIDS work.