Born in New York, Perl first graduated in chemistry in 1948 at the Brooklyn Polytechnic Institute. After working in industry as a chemical engineer for General Electric, Perl became interested in nuclear physics. Consequently he returned to college and in 1955 he was awarded his PhD from Columbia, New York. He immediately moved to the University of Michigan, where he remained until he took up the position of professor of physics at Stanford, California, in 1963.

In 1972 physicists were aware of four leptons: the electron, the muon, and their corresponding neutrinos. Further, leptons, unlike hadrons such as the proton, are genuinely pointlike elementary particles, which interact by the weak force. In 1972 Stanford opened its new accelerator, SPEAR (Stanford Positron–Electron Asymmetry Ring). While no new lepton had been found since the discovery of the muon in 1936, Perl decided to use the SPEAR facilities to see whether the lepton family could be extended.

Theoretical reasons led him to believe that any new lepton would have a charge of plus or minus 1, have a mass greater than a billion electronvolts (1 GeV), decay in less than a billionth of a second, and respond only to the weak and electromagnetic forces. Like any other particle, the new lepton would have to be identified by detecting its characteristic decay products. The particle had been named the ‘tau particle’ from the initial letter of the Greek word for third, ‘triton’. Perl argued that the tau would decay into either a muon or an electron, plus a neutrino and an antineutrino. In 1974 a sample of 10,000 events yielded twenty-four of the predicted kind. Despite some initial skepticism the existence of a heavy lepton with a mass greater than the proton was quickly confirmed.

Perl's discovery had an important theoretical implication. The four previously known leptons were linked with the four known quarks. The discovery of a new lepton, therefore, suggested the symmetry could only be maintained by the existence of a new quark. The prediction was confirmed in 1977 when Leon Lederman discovered the upsilon particle. For his discovery of the tau particle, Perl shared the 1995 Nobel Prize for physics with Frederick Reines.