He has been cast as a police officer in Artie Lange's movie Beer League, in The Sopranos, and in numerous sketches on The Chris Rock Show, where he worked as a Writer for two seasons. His writing was nominated for two Emmy Awards. He also wrote for The 77th Annual Academy Awards and the MTV Video Music Awards.

He has also been a favorite guest on radio shows including The Howard Stern Show, The Opie and Anthony Show and The Dennis Miller Show. He has filled in for Dennis Miller, Dan Patrick, Tony Bruno and others. Di Paolo hosted The Nick Di Paolo Show on 92.3 Free FM in New York City until May 24, 2007, when the station changed formats to all music. In October 2011, Di Paolo began co-hosting, with Artie Lange, the syndicated sports/entertainment talk show, The Nick & Artie Show.

Di Paolo has done USO tours in Cuba and Japan, and in 2008, Di Paolo visited Soldiers serving in Afghanistan as part of a six-person USO/Armed Forces Operation Mirth Comedy Tour with Baba Booey, Artie Lange and Dave Attell.

He was cast as the building superintendent on Louis C.K.'s HBO show Lucky Louie, and appeared with a recurring role in Louis C.K.'s FX series Louie, which began airing on June 29, 2010. In one episode, Louie aggressively argues with Di Paolo's character about the latter's dislike of Barack Obama, to the point that a physical fight breaks out and Di Paolo's character hurts his hand. Louie then takes his friend to the hospital where they have "a genuine heart-to-heart conversation about the difficulties of marriage." In the series, Louie (like his creator/portrayer) is divorced and shares joint custody of his children with his ex-wife. Di Paolo's character is "married happily, but he has no children, and his wife and he have passed that sort of point where they can't have kids and now they're faced with just each other 'til one of them is going to lose the other. And there's a melancholy feeling to that. But I envy it, because I'm alone," said C.K. in an interview.

Di Paolo has written and performed three stand up specials for Comedy Central Presents, appeared in the HBO Young Comedians Special and three hour-long comedy specials Raw Nerve, which he wrote, performed and produced. It premiered on Showtime on April 30, 2011, Another Senseless Killing, which was self-released in 2014 and Inflammatory, which was released in 2017.

As of January 2013, it was announced that Di Paolo was leaving The Nick & Artie Show to 'pursue some great opportunities'. The show was continued by Artie Lange and renamed.

He started a weekly podcast on the Riotcast network and released a new comedy special, Another Senseless Killing, in 2014.

During a 2015 interview on Marc Maron's WTF Podcast, Di Paolo described his political outlook as "center-right" (noting that he doesn't oppose social issues such as abortion and gay rights) and mentioned that his friend Colin Quinn had once quipped, "you're not a political Comedian, but you could tell a joke about McDonald's and everyone would know how you voted".

Since May 2017, Di Paolo has hosted a radio show on the satellite radio channel Faction Talk on Sirius XM Radio.

Di Paolo says he opposes political correctness, which he believes "ruined this country". Di Paolo was mentioned as part of a shock radio "brethren" in a New York Times article about CBS Radio's decision to fire Don Imus for referring to an African American college basketball player as a "nappy headed ho". The article described one of Di Paolo's bits in which he mocked an employee training manual entitled "Words Hurt and Harm", stating, "Right away, we’re starting with a false premise, because words don't hurt".