Barnard did his internship and residency at the Groote Schuur Hospital in Cape Town, after which he worked as a general practitioner in Ceres, a rural town in the Western Cape province. In 1951, he returned to Cape Town where he worked at the City Hospital as a Senior Resident Medical Officer, and in the Department of Medicine at the Groote Schuur Hospital as a registrar. During this time he completed his Masters degree, receiving Master of Medicine in 1953 from the University of Cape Town. In the same year he obtained a doctorate in medicine (MD) from the same university for a dissertation entitled "The treatment of tuberculous meningitis".
In 1956, he received a two-year scholarship for postgraduate training in cardiothoracic surgery at the University of Minnesota, Minneapolis, United States. It was during this time that Barnard first became acquainted with Norman Shumway, who did much of the pioneering research leading to the first human heart transplant. In 1958 he received a Master of Science in Surgery for a thesis entitled, "The aortic valve - problems in the fabrication and testing of a prosthetic valve". The same year he was awarded Doctor of Philosophy degree for his dissertation entitled "The aetiology of congenital intestinal atresia". Barnard described the two years he spent in the USA as "the most fascinating time in his life".
Upon returning to South Africa in 1958, Barnard was appointed cardiothoracic surgeon at the Groote Schuur Hospital, establishing the hospital's first heart unit. He was promoted to full-time lecturer and Director of Surgical Research at the University of Cape Town. Three years later he was appointed Head of the Division of Cardiothoracic Surgery at the teaching hospitals of the University of Cape Town. He rose to the position of Associate Professor in the Department of Surgery at the University of Cape Town in 1962. Barnard's younger brother Marius, who also studied medicine, eventually became Barnard's right-hand man at the department of Cardiac Surgery. Over time, Barnard became known as a brilliant surgeon with many contributions to the treatment of cardiac diseases, such as the Tetralogy of Fallot and Ebstein's anomaly. He was promoted to Professor of Surgical Science in the Department of Surgery at the University of Cape Town in 1972. Among the many awards he has received over the years, he received the title of Professor Emeritus in 1984.
Barnard performed the world's first human heart transplant operation on 3 December 1967, in an operation assisted by his brother, Marius Barnard, lasting nine hours and using a team of thirty people. The patient, Louis Washkansky, was a 54 year old grocer, suffering from diabetes and incurable heart disease. Barnard later wrote, "For a dying man it is not a difficult decision because he knows he is at the end. If a lion chases you to the bank of a river filled with crocodiles, you will leap into the water, convinced you have a chance to swim to the other side." The donor heart came from a young woman, Denise Darvall, who had been killed in a December 2, 1967, road accident while crossing a street in Cape Town. After securing permission from Darvall's father to use her heart, Barnard performed the transplant. Twenty years later, Dr. Marius Barnard recounted, "Chris stood there for a few moments, watching, then stood back and said, 'It works.'" Washkansky survived the operation and lived for eighteen(18) days. However, he succumbed to pneumonia induced by the immunosuppressive drugs he was taking. Though the first patient with the heart of another human being survived for only a little more than two weeks, Barnard had passed a milestone in a new field of life-extending surgery.
Barnard became an international superstar overnight and was celebrated around the world for his daring accomplishment. He was quite photogenic and enjoyed the media attention following the operation. Barnard continued to perform heart transplants. A transplant operation was conducted on 2 January 1968, and the patient, Philip Blaiberg, survived for 19 months. Mrs Dorothy Fisher was given a new heart in 1969 and became Barnard's longest surviving patient. She lived for 24 years after the transplant.
Barnard performed 10 orthotopic transplants (1967 – 1973). He was later also to be the first to perform a heterotopic heart transplant, an operation that he himself devised. Forty-nine consecutive heterotopic heart transplants were performed in Cape Town between 1975 and 1984.
When many surgeons, disillusioned by poor results, gave up cardiac transplantation, he persisted in his efforts until the advent of the drug Cyclosporin, which helped revive the operation throughout the world. He was also the first surgeon to attempt xenograft transplantation in a human patient, while attempting to save the life of a young girl unable to leave artificial life support after a second aortic valve replacement. He was later accused of wrongdoing by her parents.
Barnard was an outspoken opponent of South Africa's laws of apartheid, and was not afraid to criticize his nation's government, although he had to temper his remarks to some extent in order to travel abroad. Rather than leaving his homeland, he used his fame in order to campaign for a change in the law. After Denise Darvall provided the means for the very first heart transplant, Barnard transplanted her kidney into a 10 year old mixed race boy. The donor for the second heart transplant was also of mixed race. Christian's brother, Dr. Marius Barnard, went into politics, and was elected to the legislature on an anti-apartheid platform. However, he later claimed that the reason he never won the Nobel Prize in Physiology or Medicine was probably because he was a "white South African".
He had by this time become very interested in anti-aging research, and his reputation suffered in 1986 when he promoted Glycel, a two hundred dollar "anti-aging" skin cream, that was withdrawn by the United States Food and Drug Administration soon thereafter. He also spent time as a research advisor to the Clinique la Prairie, in Switzerland, where the controversial "rejuvenation therapy" was practiced. He later expressed regret for endorsing Glycel.
He divided the remainder of his years between Austria, where he established the Christiaan Barnard Foundation, dedicated to helping underprivileged children throughout the world, and his game-farm in Beaufort West, in South Africa.
Barnard died in September 2001, whilst on holiday in Paphos, Cyprus. Early reports claimed that he had died of a heart attack, although an autopsy showed his death to be caused by an acute asthma attack.
Apart from his autobiographies Dr Barnard also wrote several other books including: