He has gained recognition for his roles as Jim Neiman in the 2014 film Whiplash and Dr. Sam Owens in the Netflix series Stranger Things.

Reiser starred as one of two possible fathers of a teenage girl in the TV sitcom My Two Dads (1987–90), and later came to prominence in North America as Paul Buchman in Mad About You (1992–99), a comedy series he co-created, in which Helen Hunt co-starred as his on-screen wife.

[8] After signing onto a Mad About You revival in 2018,[9] it was picked up as a 12-episode limited series by Spectrum Originals in March 2019, which became available for members of Amazon Prime Video as of fall 2020.

[10] In 2001, Reiser played a dramatic role as a man desperate to locate his biological mother, after learning he has a serious illness, in the British TV film My Beautiful Son.

[11] In the TV comedy film Atlanta (2007), Reiser appears as one half of a couple who, after meeting at a funeral, are unable to stay away from each other.

[12] In 2010, Reiser collaborated with the singer Julia Fordham to create a CD album titled Unusual Suspects, which includes the song "UnSung Hero", dedicated to American soldiers serving in Afghanistan.

Reiser reflects about this warning and on how he then bombed at the Concord Hotel in the chapter "Don't Worry if They Suck" in I Killed: True Stories of the Road from America's Top Comics (2010), by Ritch Shydner and Mark Schiff.

However, due to the lack of lead time and promotion by NBC prior to its debut (as well as poor scheduling),[16][17] the low-rated show was canceled on April 22, 2011, with only two episodes aired.

[21] In recent years Reiser has appeared in films such as Whiplash and TV series such as Red Oaks, Stranger Things and The Boys.

Reiser has written three books: Couplehood, about the ups and downs of being in a committed relationship; Babyhood, about his experiences as a first-time father; and Familyhood (released in May 2011), a collection of humorous essays.