Perl is a 1948 chemical engineering graduate of Brooklyn Polytechnic Institute (now known as NYU-Poly) in Brooklyn. After graduation, Perl worked for the General Electric Company, as a chemical Engineer in a factory producing electron vacuum tubes. To learn about how the electron tubes worked, Perl signed up for courses in atomic physics and advanced calculus at Union College in Schenectady, New York, which led to his growing interest in physics, and eventually to becoming a graduate student in physics in 1950.

He received his Ph.D. from Columbia University in 1955, where his thesis advisor was I.I. Rabi. Perl's thesis described measurements of the nuclear quadrupole moment of sodium, using the atomic beam resonance method that Rabi had won the Nobel Prize in Physics for in 1944.

Seeking a simpler interaction mechanism to study, Perl started to consider electron and muon interactions. He had the opportunity to start planning experimental work in this area when he moved in 1963 to the Stanford Linear Accelerator Center (SLAC), then being built in California. He was particularly interested in understanding the muon: why it should interact almost exactly like the electron but be 206.8 times heavier, and why it should decay through the route that it does. Perl chose to look for answers to these questions in experiments on high-energy charged leptons. In addition, he considered the possibility of finding a third generation of lepton through electron-positron collisions.

The tau was first detected in a series of experiments between 1974 and 1977 by Perl with his colleagues at the SLAC-LBL group. Their equipment consisted of SLAC's then-new
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–
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colliding ring, called SPEAR, and the LBL magnetic detector. They could detect and distinguish between leptons, hadrons and photons. SPEAR was able to collide electrons and positrons at higher energies than had previously been possible, initially at up to 4.8 GeV and eventually at 8 GeV, energies high enough to lead to the production of a tau/antitau pair. The tau has a lifetime of only 6987290000000000000♠2.9×10 s and so these particles decayed within a few millimetres of the collision. Hence Perl and his coworkers did not detect the tau directly, but rather discovered anomalous events where they detected either an electron and a muon, or a positron and an antimuon:

Following his Ph.D., Perl spent 8 years at the University of Michigan, where he worked on the physics of strong interactions, using bubble chambers and spark chambers to study the scattering of pions and later neutrons on protons. While at Michigan, Perl and Lawrence W. Jones served as co-advisors to Samuel C. C. Ting, who earned the Nobel Prize in Physics in 1976.

Perl won the Nobel Prize in 1995 jointly with Frederick Reines. The prize was awarded "for pioneering experimental contributions to lepton physics". Perl received half "for the discovery of the tau lepton" while Reines received his share "for the detection of the neutrino".

He joined University of Liverpool as a visiting professor. He served on the board of advisors of Scientists and Engineers for America, an organization focused on promoting sound science in American government. In 2009, Perl received an honorary doctorate from the University of Belgrade.

He died after a heart attack at Stanford University Hospital on September 30, 2014 at the age of 87.