In 1929, after receiving his degree from Kyoto Imperial University, he stayed on as a lecturer for four years. After graduation, he was interested in theoretical physics, particularly in the theory of elementary particles. In 1932, he married Sumi Yukawa (スミ). In accordance with Japanese customs of the time, since he came from a family with many sons but his father-in-law Genyo had none, he was adopted by Genyo and changed his family name from Ogawa to Yukawa. The couple had two sons, Harumi and Takaaki. In 1933 he became an assistant professor at Osaka University, at 26 years old.

In 1935 he published his theory of mesons, which explained the interaction between protons and neutrons, and was a major influence on research into elementary particles. In 1940 he became a professor in Kyoto University. In 1940 he won the Imperial Prize of the Japan Academy, in 1943 the Decoration of Cultural Merit from the Japanese government. In 1949 he became a professor at Columbia University, the same year he received the Nobel Prize in Physics, after the discovery by Cecil Frank Powell, Giuseppe Occhialini and César Lattes of Yukawa's predicted pi meson in 1947. Yukawa also worked on the theory of K-capture, in which a low Energy electron is absorbed by the nucleus, after its initial prediction by G. C. Wick.

He was an Editor of Progress of Theoretical Physics, and published the books Introduction to Quantum Mechanics (1946) and Introduction to the Theory of Elementary Particles (1948).

Yukawa became the first chairman of Yukawa Institute for Theoretical Physics in 1953. He received a Doctorate, honoris causa, from the University of Paris and honorary memberships in the Royal Society, Royal Society of Edinburgh, the Indian Academy of Sciences, the International Academy of Philosophy and Sciences, and the Pontificia Academia Scientiarum.

In 1955, he joined ten other leading Scientists and intellectuals in signing the Russell–Einstein Manifesto, calling for nuclear disarmament.

Yukawa retired from Kyoto University in 1970 as a Professor Emeritus. Owing to increasing infirmity, in his final years he appeared in public in a wheelchair. He died at his home in Sakyo-ku, Kyoto, on 8 September 1981 from pneumonia and heart failure, aged 74. His tomb is in Higashiyama-ku, Kyoto.