He is best known for his work as a writer on Saturday Night Live and as a stand-up comedian with stand-up specials The Top Part (2009), New in Town (2012),
The Comeback Kid (2015), and Kid Gorgeous (2018), for which he won the Primetime Emmy Award for Outstanding Writing for a Variety Special.
Mulaney is also known for his children's musical comedy special John Mulaney & the Sack Lunch Bunch (2019) which was released on Netflix.
He was the creator and star of the short-lived Fox sitcom Mulaney (2014–2015), a semi-autobiographical series about his life.
He is also known for his voice acting work as Andrew Glouberman in the Netflix original animated show Big Mouth.