He was a very active member of the international ComedySportz troupe (a comic improvisation team that participates in games as seen on Whose Line Is It Anyway?).  Having joined All That‘s cast at the start of its 7th season in 2002, he subsequently tied with Logan Lerman for the 2005 Young Artist Award for Best Performance in a TV Series (Comedy or Drama) – Leading Young Actor. He rapidly gained recognition for his skilled and clever ad-libbing from his work as Sokka on Avatar: The Last Airbender and also guest starred as Jimmy Olsen in The Batman.

De Sena worked on the online mockumentary web series Dorm Life, a 2008 Webby Honoree for Best Writing and Comedy: Individual Short or Episode. De Sena appeared on an episode of King of the Hill, “Luanne Gets Lucky.” De Sena has also appeared in an episode of Generator Rex, “Crash and Burn.” In 2012, De Sena appeared on the Hulu original series Battleground.  In 2013, he appeared as the judge of the texting competition and later as an airport investigator on the Nickelodeon sitcom Sam & Cat. In 2014, he voiced Robin in the animated film JLA Adventures: Trapped in Time.

He has also portrayed “Mr. Roberts” in the television series 100 Things to Do Before High School from 2014 to 2016.

Since January 19, 2016, he and his longtime friend Chris W. Smith have been creating and starring in comedy sketches on their YouTube channel “Chris and Jack”.

From 2018 to 2024, he was the voice of Callum on the Netflix animated series The Dragon Prince.