At 14, Perlin began studying art under Burne Hogarth, who taught small private classes prior to co-founding the Cartoonists and Illustrators School. In 1951, Perlin was a penciller on Will Eisner's The Spirit. Perlin was drafted in 1953 and served in the United States Army.

The artist drew one title for Gilberton's Classics Illustrated series, No. 162, Robur the Conqueror, an adaptation of a Jules Verne novel about a power-mad genius and his "flying apparatus." The comic book was published in May 1961, the first of three printings.

In 1974 he began a long association with Marvel, where he was a full-time penciler until 1987. From 1980—1986, he was the regular (and longest-serving) artist on Defenders. In addition to his work on The Defenders, Werewolf by Night, and Ghost Rider, Perlin penciled Transformers. Perlin's Werewolf run is notable for introducing the character of Moon Knight, who he co-created with writer Doug Moench. In the late 1980s Perlin became a managing art director at Marvel, overseeing younger artists.

Perlin left the Marvel managing art direction position in 1991 to became a major part of Jim Shooter's Valiant Comics team. Besides penciling the popular series Solar, Man of the Atom and Bloodshot, Perlin also edited (among others) titles like Shadowman, Magnus Robot Fighter, and Solar. Shortly after Valiant's mid-90s demise (and takeover by Acclaim Entertainment), Perlin went into semi-retirement.

Perlin won the 1997 National Cartoonists Society Comic Books Award.