He is the host of the Misery Loves Company podcast, and is best known for his work on Saturday Night Live's Weekend Update in 1999 and 2000.

[3][4] Brennan was voted "Best Comedian" at the 2005 Aspen Comedy Festival and his half-hour stand-up special was featured on HBO that same year.

[11][12] In 1993, Brennan appeared on the entertainment competition show Star Search where he competed unsuccessfully against 19-year-old Dave Chappelle.

[17] That same year the Brennan brothers had a development deal with NBC and Universal for a sitcom based on their own experiences growing up in an Irish-Catholic family with 10 kids in Philadelphia.

[21][22] Brennan was voted “Best Comedian” at the 2005 Aspen Comedy Festival, which lead to his half-hour stand-up special on the HBO series One Night Stand that same year.

[6] Brennan started the comedic podcast titled Misery Loves Company (MLC) in January 2016, and added fellow New York-based comedian Lenny Marcus as his co-host.

[31] Roasters at the event included comedians Dan Soder, Jim Norton (in character as Chip Chipperson), Krystyna Hutchinson and Corinne Fischer of the Guys We Fucked podcast, Patty Rosborough, Chad Zumock and Mike Bocchetti.

[3] Brennan drew public criticism for his remarks about the unexpected death of Friends actor Matthew Perry on social media, in late October 2023.