Dr. John A. Clements, a towering figure in the field of pulmonary research who in the 1950s solved one of the great mysteries of the human lung, then helped to save thousands of lives by designing a drug to treat lung failure in premature infants, died on Sept. 3 at his home in Tiburon, Calif., north of San Francisco. He was 101.

The death was confirmed by his daughter Carol Clements.

In 1949, Dr. Clements was fresh out of Cornell University Medical College (now Weill Cornell Medical College) and working for the Army as a physiologist when he became intrigued by the miraculous mechanics of human breathing.

How could the millions of tiny air sacs in the lungs deflate when a person breathes out, but not collapse like a balloon? Dr. Clements theorized that there must be some chemical relaxing the surface tension of the air sacs, and he went on to identify the substance as a surfactant, a class of lubricants that work like household detergents.

In a 1956 paper, based on research done with a crude instrument he built himself, Dr. Clements demonstrated the presence of a surfactant in the lungs.

His work led to a breakthrough three years later by two Harvard researchers whom Dr. Clements advised: Pulmonary surfactant, they found, was absent in premature babies with undeveloped lungs who died of respiratory distress syndrome, or R.D.S.

The condition was once the leading cause of neonatal mortality in the United States, responsible for about 10,000 deaths annually in the 1960s.

One high-profile R.D.S. death was Patrick Bouvier Kennedy, the second son of President John F. Kennedy and Jacqueline Kennedy, who was born five and a half weeks prematurely in August 1963 and died within days.

“Back in the 1950s and early ’60s, if they had full-blown respiratory distress syndrome, more than 90 percent would die,” Dr. Clements said in a 2017 interview with iBiology Science Stories, a YouTube channel.

The discovery that premature babies lacked lung surfactant set off a worldwide rush to find a treatment. Some researchers tried replacement surfactants derived from sheep and cow lungs, but Dr. Clements believed animal surfactants were risky for tiny babies.

So, in response to a request from the premature infant nursery at the University of California, San Francisco, where he was a professor of pulmonary biology and pediatrics, Dr. Clements set out to develop a synthetic surfactant.

“It sounds incredibly naïve, or maybe at the other pole, really arrogant,” he said in a 2017 interview published on the university’s website, “but I said, ‘Well, I’ll make one for you’ — trying to accomplish in a few weeks or months what had taken divine providence millions of years — if you believe in evolution.”

His research led to the first synthetic lung surfactant, which the University of California licensed to the drugmaker Burroughs Wellcome and Company. Its drug Exosurf was the first replacement surfactant for clinical use approved by the Food and Drug Administration, in 1990.

Eventually, further study found that animal-derived surfactants worked better, and they are most often used today. Infant deaths from R.D.S. in the United States have declined to fewer than 500 a year.

In 1994, Dr. Clements won the Albert Lasker Clinical Medical Research Award for what was “widely regarded as the most important discovery in pulmonary physiology in the last 50 years,” according to the award citation.

Dr. Jordan U. Gutterman, the head of the awards at the time, noted how extraordinary it was for a scientist to be responsible for both a breakthrough in basic research and the development of a marketable treatment.

“It’s an incredible story of one man who looked at a problem and studied the physiology” and then solved the problem, he told The New York Times.

Dr. Clements donated the $25,000 in prize money to UNICEF.

John Allen Clements was born on March 16, 1923, in Auburn, N.Y., in the Finger Lakes region, the youngest of four children of Harry, a lawyer, and May Victoria (Porter) Clements. Both parents encouraged his childhood interest in scientific experiments. He rigged a shoe box with a flashing light that read “Scientist” and hung it in the window of the house. He made his own Tesla coil from scrounged-up parts, which the police told him he had to switch off after 6 p.m. because it was interfering with the neighbors’ radio.

Dr. Clements took advantage of an Army-paid accelerated program to complete his undergraduate work and an M.D. in five and a half years from Cornell. After his graduation in 1947, he worked for the Army Chemical Center in Maryland.

In 1949, he married Margot S. Power, a classical singer who went on to perform with the Baltimore Symphony, the Marin Symphony and the Carmel Bach Festival.

She died in 2022. In addition to their daughter Carol, Dr. Clements is survived by another daughter, Christine Clements.

At the University of California, San Francisco, which recruited Dr. Clements in 1959, he trained generations of physicians and researchers in his pulmonology lab.

After he retired in 2004, and into his 90s, he continued to drive to an office at the university two or three days a week, where he pursued research and advised others.

He parked his car in the same space for 50 years. Carol Clements said it exemplified his depth of focus: His laboratory work was always on his mind, and if he had parked in a different place, he would never be able to remember where.