Propelled by an intense boyhood curiosity and love for nature and mathematics, he graduated valedictorian from the Columbia Grammar & Preparatory School and subsequently entered Yale College at the age of 15 as a member of Jonathan Edwards College. At Yale, he participated in the william Lowell Putnam Mathematical Competition and was on the team representing Yale University (along with Murray Gerstenhaber and Henry O. Pollak) that won the second prize in 1947. Gell-Mann earned a bachelor's degree in physics from Yale in 1948 and a PhD in physics from Massachusetts Institute of Technology (MIT) in 1951. His supervisor at MIT was Victor Weisskopf.

Gell-Mann's work in the 1950s involved recently discovered cosmic ray particles that came to be called kaons and hyperons. Classifying these particles led him to propose that a quantum number called strangeness would be conserved by the strong and the electromagnetic interactions, but not by the weak interactions. Another of Gell-Mann's ideas is the Gell-Mann–Okubo formula, which was, initially, a formula based on empirical results, but was later explained by his quark model. Gell-Mann and Abraham Pais were involved in explaining several puzzling aspects of the physics of these particles.

He was a postdoctoral fellow at the Institute for Advanced Study in 1951, and a visiting research professor at the University of Illinois at Urbana–Champaign from 1952 to 1953. He was a visiting associate professor at Columbia University and an associate professor at the University of Chicago in 1954–55 before moving to the California Institute of Technology, where he taught from 1955 until he retired in 1993.

In 1958, Gell-Mann and Richard Feynman, in parallel with the independent team of George Sudarshan and Robert Marshak, discovered the chiral structures of the weak interaction in physics. This work followed the experimental discovery of the violation of parity by Chien-Shiung Wu, as suggested by Chen Ning Yang and Tsung-Dao Lee, theoretically.

In 1961, this led him (and Kazuhiko Nishijima) to introduce a classification scheme for hadrons, elementary particles that participate in the strong interaction. (This scheme had been independently proposed by Yuval Ne'eman.) This scheme is now explained by the quark model. Gell-Mann referred to the scheme as the Eightfold Way, because of the octets of particles in the classification. (The term is a reference to the eightfold way of Buddhism.)

In 1964, Gell-Mann and, independently, George Zweig went on to postulate the existence of quarks, particles of which the hadrons of this scheme are composed. The name was coined by Gell-Mann and is a reference to the novel Finnegans Wake, by James Joyce ("Three quarks for Muster Mark!" book 2, episode 4.) Zweig had referred to the particles as "aces", but Gell-Mann's name caught on. Quarks, antiquarks, and gluons were soon established as the underlying elementary objects in the study of the structure of hadrons. He was awarded a Nobel Prize in physics in 1969 for his contributions and discoveries concerning the classification of elementary particles and their interactions.

Gell-Mann, along with Maurice Lévy, developed the sigma model of pions, which describes low-energy pion interactions. Modifying the integer-charged quark model of Moo-Young Han and Yoichiro Nambu, Harald Fritzsch and Gell-Mann were the first to write down the modern accepted theory of quantum chromodynamics, although they did not anticipate asymptotic freedom. In 1969 he received the Nobel Prize in physics for his contributions and discoveries concerning the classification of elementary particles and their interactions.

Gell-Mann is responsible, together with Pierre Ramond and Richard Slansky, and independently of Peter Minkowski, Rabindra Mohapatra, Goran Senjanovic, Sheldon Lee Glashow, and Tsutomu Yanagida, for the seesaw theory of neutrino masses, that produces masses at the large scale in any theory with a right-handed neutrino. He is also known to have played a large role in keeping string theory alive through the 1970s and early 1980s, supporting that line of research at a time when it was unpopular.

In 1972 he and Harald Fritzsch introduced the conserved quantum number "color charge", and later, together with Heinrich Leutwyler, they coined the term quantum chromodynamics (QCD) as the gauge theory of the strong interaction. The quark model is a part of QCD, and it has been robust enough to accommodate in a natural fashion the discovery of new "flavors" of quarks, which superseded the eightfold way scheme.

Gell-Mann married J. Margaret Dow (d. 1981) in 1955: their children are Elizabeth Sarah Gell-Mann (b. 1956) and Nicholas Webster Gell-Mann (b. 1963). Margaret died in 1981, and in 1992 he married Marcia Southwick, with whom he has a stepson, Nicholas Southwick Levis (b. 1978).

He is currently the Robert Andrews Millikan Professor of Theoretical Physics Emeritus at California Institute of Technology as well as a University Professor in the Physics and Astronomy Department of the University of New Mexico in Albuquerque, New Mexico, and the Presidential Professor of Physics and Medicine at the University of Southern California. He is a member of the editorial board of the Encyclopædia Britannica. In 1984 Gell-Mann co-founded the Santa Fe Institute—a non-profit theoretical research institute in Santa Fe, New Mexico—to study complex systems and disseminate the notion of a separate interdisciplinary study of complexity theory.

During the 1990s, Gell-Mann's interest turned to the emerging study of complexity. He played a central role in the founding of the Santa Fe Institute, where he continues to work as a distinguished professor.

Gell-Mann endorsed Barack Obama for the United States presidency in October 2008.

The author George Johnson has written a biography of Gell-Mann, Strange Beauty: Murray Gell-Mann, and the Revolution in 20th-Century Physics, which was shortlisted for the Royal Society Book Prize. Gell-Mann has criticized it as inaccurate. The Nobel Prize–winning Physicist Philip Anderson, in his chapter on Gell-Mann, says that Johnson's biography is excellent. Both Anderson and Johnson say that Gell-Mann is a perfectionist and that his semibiographical, The Quark and the Jaguar is consequently incomplete.

Gell-Mann introduced, independently of George Zweig, the quark—constituents of all hadrons—having first identified the SU(3) flavor symmetry of hadrons. This symmetry is now understood to underlie the light quarks, extending isospin to include strangeness, a quantum number which he also discovered.