He is known for his roles in the films Licorice Pizza, Booksmart, and Vacation, as well as the television programs Psych, The Righteous Gemstones, and Santa Clarita Diet.

[4] He spent a number of years in high school heavily involved in the Jewish community, including participating in USY, and attending Camp Alonim in Simi Valley.

In 2003, Gisondo made his first appearance on television, playing Jeffrey in the comedy-drama series Miss Match in the episode "Forgive and Forget".

[16][17] In 2011, Gisondo played live action as Billy and voice role of B-Dawg in the supernatural comedy film Spooky Buddies, the fifth installment in the Air Buddies series,[18] he won the Best Performance in a DVD Film - Young Ensemble Cast shared with Tucker Albrizzi, Sierra McCormick, Jake Johnson and Sage Ryan at the 33rd Young Artist Awards.

[21] Gisondo played the role of Howard Stacy in the 2012 American superhero film by Marc Webb titled The Amazing Spider-Man.

Gisondo was cast in the 2014 fantasy comedy film by Shawn Levy's titled Night at the Museum: Secret of the Tomb starring Ben Stiller, Robin Williams, Owen Wilson, Rami Malek and Dan Stevens, in which he played the role of Nicholas "Nick" Daley.

[24][25] In 2015, Gisondo starred in the road comedy movie Vacation opposite Ed Helms, Christina Applegate and Steele Stebbins, which was released on July 29, 2015.

[26][27] In 2016, Gisondo starred along with Katrina Bowden and Kristin Chenoweth in the comedy-drama movie Hard Sell written and directed by Sean Nalaboff, which was released on May 20, 2016.

He starred opposite Alex Wolff, Mike Epps, Tommy Nelson and Stefania LaVie Owen in the coming-of-age drama film The Cat and the Moon portraying Seamus.

[46] From 2021 to 2022, Gisondo starred alongside Kiersey Clemons, Peter S. Kim and Jaboukie Young-White in the adult animated comedy series Fairfax, in which he played the lead role as Dale.