[1][5] He has said that he realized he was funny and liked comedy at about 8 or 9 years of age, and had already been performing material for his classmates in a style that emulated comedians David Brenner, Richard Lewis, and Jerry Seinfeld.

[7] Brennan would spend weekends attending Kevin's performances at The Improv in New York City,[1] where he would meet comedians such as Dave Attell, David Juskow, Ray Romano, and Mike Royce.

[7][8][9] He began as a doorman at the now-defunct Boston Comedy Club in Greenwich Village where he met frequent performer Dave Chappelle.

"[8] In an interview that same year on Inside the Actors Studio, Chappelle recounted how he and Brennan lost touch with each other after the release of Half Baked, saying that it was "like leaving a crime scene".

"[31][33] In 2011, Brennan, comedian Moshe Kasher, and DJ Douggpound (Doug Lussenhop) started a podcast called The Champs.

[34][35] Kasher said of the podcast: "It's Doug dropping sound effects and beats over me and Neal kind of hosting an hour of ridiculous chat.

"[34] Guests on the show included actor/comedians Wayne Brady, Chris Rock, Mario Joyner, Shawn and Marlon Wayans, David Alan Grier, adult film star Lexington Steele, rapper Too $hort, and professional basketball player Blake Griffin.

On occasion the show has strayed from its regular format with guests such as comedian and actor Bobby Lee, former pornographic actress Sasha Grey, former Major League Baseball player Jose Canseco, and comedian/actor Aziz Ansari.

In August 2021, Brennan's one-man show Unacceptable debuted at New York City's Cherry Lane Theater with acclaimed magician, author, artist Derek DelGaudio as director.

It follows the same format as his Netflix special (of the same name) in that he asks his guests about aspects of their life that leave them isolated or lonely and how they overcome these “blocks”.

[12] Brennan has also written comedy material for the 83rd Academy Awards, as well as for Seth Meyers's speech at the White House Correspondents' Dinner in 2011.

On October 10, 2019, he was featured in a 30-minute YouTube documentary created by SoulPancake in collaboration with Funny or Die called Laughing Matters, wherein a variety of comedians discuss mental health.

[47] Brennan has said that his comedy influences are Chris Rock,[4] Mort Sahl,[4] Dave Attell,[8] Mike Royce,[8] and David Juskow.

In an episode of his Blocks podcast he puts comedian Jimmy Carr in the host’s seat and they discuss how he was helped by use of ayahuasca.