Shimerman was born to a Jewish family in Lakewood, New Jersey, the son of Susan, an accountant, and Herbert Shimerman, a house painter. When Shimerman was 15, his family moved to Los Angeles, where his mother enrolled him in a drama group in an effort to expand his social circle. He played trumpet in the Santa Monica High School Band. He graduated from the University of California, Los Angeles, then was selected to apprentice at the Old Globe Theater in San Diego. He pursued a dramatic career in theater, eventually moving to New York. Returning to Los Angeles he received roles in two CBS series, launching his television acting career.
Shimerman is best known for his role as the Ferengi bar owner Quark in the long-running television series Star Trek: Deep Space Nine, though his involvement with the Star Trek franchise began with appearances as other Ferengi characters in the Star Trek: The Next Generation episodes "The Last Outpost" and "Peak Performance". As the character Quark, Shimerman became one of Star Trek's most widely known characters, and he appeared several times on the cover of TV Guide, either with other actors or alone as part of a collector's series. He says that his favorite episode of Deep Space Nine is "Little Green Men" as it was the only episode where he is shown captaining a ship.
Along with Marina Sirtis, Jonathan Frakes, John de Lancie, Michael Ansara, and Richard Poe, he is one of only a few actors to play the same character on three different Star Trek series. He played Quark in Star Trek: The Next Generation, Star Trek: Deep Space Nine, and Star Trek: Voyager.
In addition to Star Trek, Shimerman has had roles as Pascal on Beauty and the Beast and as Principal Snyder in Buffy the Vampire Slayer. He also has starred in Stargate SG-1 as one of the Nox, an evil wizard in Charmed, appeared as Stan The Caddy in an episode of Seinfeld, and as Dr. Patemkin on Leverage.
Shimerman has appeared as judge Brian Hooper in the third season of Boston Legal, joining fellow Star Trek actors William Shatner, Rene Auberjonois, and Ethan Phillips; Shatner played Captain Kirk on Star Trek, Auberjonois played Odo on Star Trek: Deep Space Nine, and Phillips played Neelix on Star Trek: Voyager. His character even shared a scene with Auberjonois, with the strife between the two characters reminiscent of the conflict between Shimerman's Quark and Auberjonois's Odo.
Shimerman made an appearance as "The Terror" in The Tick live action series.
He appeared in the series Numb3rs episode 'Provenance' as an art expert. He also appeared in the episode "Posse Comitatus" of The West Wing as Richard III, and had a cameo role in both What the Bleep movies.
He also appeared in the episode "Buck the Stud" of Married... with Children.
Shimerman also appeared in the episode "Where and When" of the TV series Warehouse 13. He played the character Charlie Martin, that episode's version of Artie Nielsen.
He also appeared in the episode "A Little Paranoia Among Friends" as radio personality Cecil Carr in the short-lived Tremors TV series.
In 2012 he also appeared on Castle in the episode "The Final Frontier".
In 2016, appeared as Max in the Western web series Red Bird.
He has voiced several video game villains, including Toad in X-Men Legends, Andrew Ryan in the BioShock series, Razputin's father in Psychonauts, and General Skarr from Evil Con Carne and The Grim Adventures of Billy and Mandy. He lent his voice talent to BioWare for their games Jade Empire (as Emperor Sun Hai) and Mass Effect (as the original Salarian Councillor). He also voices Emil Narud and Mohandar in StarCraft II: Wings of Liberty and the expansion StarCraft II: Heart of the Swarm.
In 2008, he voiced the character of Wilmer in an audio dramatization of The Maltese Falcon that also featured Michael Madsen, Sandra Oh, and Edward Herrmann. In addition, he also voiced the character of Mr. Phillips in Focus on the Family Radio Theatre's production of Anne of Green Gables. He also voiced Raanu in the straight-to-DVD feature animation Bionicle: The Legend Reborn. He also voices Green Goblin in the video game Marvel Ultimate Alliance 2.
In 2011, he also starred in a voice-over part for a character on the MMORPG Star Wars: The Old Republic.
In 2012, he starred in a voice-over part for a character on the MMORPG The Secret World. He also voiced both Dr. Nefarious and Andrew Ryan in the crossover, PlayStation All-Stars Battle Royale.
His most well known voice role is that of Dr. Nefarious in Ratchet & Clank: Up Your Arsenal, Ratchet: Deadlocked, Ratchet & Clank: Quest for Booty, Ratchet & Clank Future: A Crack in Time, Ratchet & Clank: All 4 One and Ratchet & Clank (2016 video game), a role he received much praise for.
Shimerman has co-written a series of books in which he provides a science fictional basis for the life of Dr. John Dee. The first novel in the series, The Merchant Prince, was co-written with Irish author Michael Scott, known for his Nicholas Flamel series. Published in 2000, it features the historical figure John Dee being placed in suspended animation in 1575 by an alien race known as the Roc and awakening in 2099. The cover features Shimerman in Elizabethan garb.
Shimerman commented: "John Dee really did exist. We're pretty sure he was a member of Queen Elizabeth's secret service, which put it in his purview to kill if he needed to. The Elizabethan period was a much more perilous time; you had to be quick with a dagger and nefarious in order to survive".
Shimerman thought there were aspects of both himself and his Star Trek: Deep Space Nine character, Quark, in the novel's interpretation of John Dee. Shimerman commented: "There are aspects of Quark similar to Dr. Dee, and undoubtedly there are aspects of Dr. Dee similar to Armin Shimerman, which would make him seem like Quark as well".
The other novels in the series are Outrageous Fortune (2002), co-written with Chelsea Quinn Yarbro, known for her historical horror novels, and Capital Offense (2003).
Shimerman is married to actress Kitty Swink.