He is known for his roles as Billy Chenowith in HBO's Six Feet Under, NYPD Detective Cyrus Lupo in NBC's Law & Order, George Altman in the ABC sitcom Suburgatory, for which he was nominated for a Critics' Choice Television Award for Best Actor in a Comedy Series, and Jubal Valentine in the CBS drama series FBI.

In 2004, he portrayed bigoted baseball player Shane Mungitt in Take Me Out, for which he was nominated for a Los Angeles Drama Critics Circle Award for Featured Performance in a Play.

[5] Sisto made his film debut in the 1991 drama Grand Canyon, starring Kevin Kline and Steve Martin.

In his early film and television career, Sisto played a killer in Hideaway (1995); a rich teen in Clueless (1995); a 20-something kidnapper in Suicide Kings (1997); Olympic gold medalist long-distance runner Frank Shorter in Without Limits (1998); Jesus Christ in the CBS miniseries Jesus (1999); and a widowed filmmaker in This Space Between Us (1999).

In 1996, Sisto screen tested for the character of Jack Dawson in the James Cameron film Titanic alongside Kate Winslet but ultimately lost out on the role to Leonardo DiCaprio.

For that work, he was twice nominated for the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series along with his co-stars.

[18] The following year, he starred in the Manhattan Theatre Club production of Spirit Control at the New York City Center, gaining rave reviews for his performance as Adam Wyatt.

[23] The following year, Sisto co-starred as Guy Karlsburg, alongside James Marsden and Claire Danes, in the comedy-drama As Cool as I Am.

[27] In 2015, Sisto produced and starred as Aaron Miller in the British thriller film Hangman, which had its premiere at South by Southwest.

Sisto portrayed Detective Jack Roth, an LAPD officer searching for a serial killer on the Sunset Strip.

Sisto was then cast alongside Archie Panjabi in ABC's drama pilot The Jury, but the project was not picked up to series.

[30] From 2016 to 2018, Sisto starred as Freddy Green in Antoine Fuqua's Audience Network drama series Ice, opposite Cam Gigandet and Donald Sutherland.

[31] Sisto currently portrays Assistant Special Agent-in-Charge Jubal Valentine in Dick Wolf's CBS drama series FBI.