He is said to have performed more than 60,000 heart surgeries during his 70-year career, including on famous names such as late American presidents John F. Kennedy, Lyndon Johnson and Richard Nixon, the last Shah of Iran and King Hussein of Jordan.
He also invented mobile army surgical hospital (MASH) units and performed a series of surgical firsts -- including the some of the first heart transplants, removal of artery blockages and bypass operations.
DeBakey died of natural causes late Friday, according to the DeBakey Heart and Vascular Center at Methodist Hospital in Houston.
He "improved the human condition and touched the lives of generations to come," Ron Girotto, president of The Methodist Hospital System, said in a statement.
"Dr DeBakey's reputation brought many people into this institution, and he treated them all: heads of state, entertainers, businessmen and presidents, as well as people with no titles and no means," said Girotto.
As recently as two years ago, when he was 97, DeBakey was a senior attending surgeon at Methodist Hospital, the largest hospital in the Texas Medical Center, and chancellor emeritus of Baylor College of Medicine, a leading center for medical education and research.
DeBakey has been described as "an ingenious medical inventor and innovator, a gifted and dedicated teacher, a premier surgeon, and an international medical statesman" by his colleagues at Methodist Hospital.
He earned his undergraduate and medical degrees from Tulane University in New Orleans, Louisiana, and was a resident in surgery at the University of Strasbourg, France, and at the University of Heidelberg, Germany.
While still in medical school, DeBakey invented the roller pump, which would become a major component of the heart-lung machine used in open-heart surgery.
He also led the way in performing many groundbreaking surgeries, including the first removal of a carotid artery blockage in 1950; the first aorto-coronary bypass surgery (1964); the first use of a ventricular assist device to pump blood and support a diseased heart in 1966; and some of the first US heart transplants (1968-69).
In 1969, he received the Presidential Medal of Freedom with Distinction, the highest honor that can be bestowed on a US citizen.
DeBakey was also awarded the prestigious UN Lifetime Achievement Award in 1999 and a was recognized by the US Library of Congress as a "Living Legend" the following year.
In April of this year, DeBakey was awarded the Congressional Gold Medal, the highest civilian award bestowed by the US Congress to those who "have made an impact on the world."
Only 196 Congressional Gold Medals have been awarded since 1776, putting DeBakey in the company of the first president of the United States, George Washington; former British prime minister Winston Churchill; South African former president Nelson Mandela; and the late Pope John Paul II.