His breakthrough came with the leading role as FDNY Paramedic Roberto "Bobby" Caffey in the NBC series Third Watch, which he played from 1999 to 2001.

[2] He won the Primetime Emmy Award for Outstanding Supporting Actor in a Drama Series for portraying Gyp Rosetti in Boardwalk Empire in 2013.

He has also starred in the Amazon Prime series Homecoming (2018–20), the Hulu miniseries Nine Perfect Strangers (2021), and Netflix's The Watcher (2022).

He has also been in comedic films, such as Paul Blart: Mall Cop (2009), The Other Guys (2010), Annie (2014), Spy (2015), and Jumanji: Welcome to the Jungle (2017).

[7] When he was eight, Cannavale secured the plum role of the lisping boy, Winthrop, in his school's production of The Music Man and later played a gangster in Guys and Dolls, which cemented his love for performing.

From 2004 to 2006, he had a recurring guest role on Will & Grace as Vince D'Angelo, the boyfriend (and eventual husband) of Will Truman (Eric McCormack).

On August 25, 2008, ABC ordered his pilot Cupid, a remake of the 1998 program which had starred Jeremy Piven and Paula Marshall, to series.

His performance on Boardwalk Empire won critical acclaim, earning him the Primetime Emmy Award for Outstanding Supporting Actor in a Drama Series in 2013.

That same year he also played Lewis, a vengeful clown on Modern Family during the third season, for which he was nominated for Best Guest Performer in a Comedy Series at the 2nd Critics' Choice Television Awards in 2012.

[20] TV Guide, in its "Cheers & Jeers 2012" issue, praised Cannavale for this "trifecta of great performances", commenting, "This guy is so good at playing bad, it's scary.

[23][24][25] In January 2020, Cannavale appeared with his real-life partner Rose Byrne in the play Medea, written and directed by Simon Stone.

[26][27] In 2021, Cannavale played Tony Hogburn in the Nicole Kidman led Hulu miniseries Nine Perfect Strangers (based on the novel of the same name by Liane Moriarty), which also featured Melissa McCarthy, Michael Shannon, Luke Evans, Samara Weaving, and Asher Keddie.