Prinze was born in Los Angeles, California, the son of Italian American Katherine Elaine Cochran (a real-estate agent) and Freddie Prinze, a half German-American and half Puerto Rican-American actor and comedian who died in 1977.  Prinze's paternal grandfather Karl Pruetzel was a German immigrant and his paternal grandmother was Puerto Rican; he was raised a Roman Catholic and embraces his Puerto Rican heritage.

 Prinze was cast in a guest role on the ABC TV series Family Matters in 1995. He then appeared on a few special programs and made-for-TV movies, before making his motion picture debut in "To Gillian on Her 37th Birthday" in 1996.In subsequent years, Prinze experienced much success appearing in youth-oriented movies." I Know What You Did Last Summer" (1997) and its sequel, I "Still Know What You Did Last Summer" (1998), made him well-known among teenage audiences and his first leading role, the romantic comedy She's All That (1999), was very successful at the box office, grossing $63 million in the United States.

Subsequently, Prinze had leading roles in Wing Commander (1999), Down to You (2000), Boys and Girls (2000), Head Over Heels (2001) and Summer Catch (2001), most of which were generally disliked by critics [4] and had moderate box office performances . In 2000, he was named one of People magazine's "50 Most Beautiful People in the World".

In 2002, he played Fred Jones in the live film version of the popular cartoon, Scooby-Doo, and repeated the role in the 2004 sequel, Scooby-Doo 2: Monsters Unleashed. He starred in both Scooby-Doo movies alongside his wife, Sarah Michelle Gellar. He guest starred on the popular NBC show, Friends, as a sensitive male nanny named Sandy. He also appeared as Donny Crane, a character believed to be Denny Crane's son in the ABC legal drama Boston Legal.

Prinze starred in his own television sitcom, titled Freddie. The sitcom is said to depict some actual events from his life. The show lasted one season (fall 2005 - spring 2006) before being canceled in May 2006.

Prinze is also featured in the Marvel Comics series The Ultimates, though his face is always obscured. His date with Betty Banner, the Hulk's ex-wife, infuriates the Hulk, prompting him to go on a destructive rampage through New York City that results in the deaths of approximately 800 people.