[9] Spiner moved to New York City in the early 1970s,[10] where he became a stage actor, performing in several Broadway and off-Broadway plays, including The Three Musketeers and Stephen Sondheim's Sunday in the Park with George.

In 1986, he played a condemned soul in "Dead Run", an episode of the revival of Rod Serling's series The Twilight Zone on CBS.

He also appeared in the Tales from the Darkside episode "A Case of the Stubborns" as a preacher, and portrayed Jim Stevens in the television film Manhunt for Claude Dallas.

[12] In 1987, Spiner was cast as android Starfleet officer Lieutenant Commander Data on Star Trek: The Next Generation, which spanned seven seasons and four feature films.

[20] In 1997, he returned to Broadway as John Adams in the Roundabout Theater Company revival of the musical 1776, whose production was nominated for a Tony Award.

[21] Spiner has appeared in many television series, including Deadly Games, The Blacklist, Dream On, Gargoyles, Law & Order: Criminal Intent, Mad About You and The Outer Limits.

[citation needed] In 2005, Spiner appeared in a short-lived science-fiction television series Threshold, which was canceled in November of that year after 13 episodes.

In February 2009, he played William Quint in "The Juror #6 Job", an episode of the drama series Leverage directed by his Next Generation co-star Jonathan Frakes.

[citation needed] On January 13, 2010, Spiner and fellow Star Trek: The Next Generation actor LeVar Burton appeared on TWiT.tv's coverage of the Consumer Electronics Show.

[25] In April 2011, Spiner began starring in Fresh Hell, a comic webseries in which he plays a version of himself, attempting to put his career back together after falling out of the limelight.

[citation needed] In March 2024, Spiner reprised his role of the eternally downtrodden Bob Wheeler, in the 11th episode of the second season of Night Court.

In October 2021, Spiner released Fan Fiction: A Mem-Noir: Inspired by True Events, a mixture of memoir (taking place during the filming of the fourth season of Star Trek: The Next Generation) and a fictitious noir detective story about Spiner dealing with a crazed, murderous fan who claims to be the fictitious Lal, the android daughter of Data in the third-season TNG episode "The Offspring".