Jerry O'Connell was born in New York City, to Linda (Witkowski), an art teacher, and Michael O'Connell, a British-born advertising agency art director. He spent his early years in Manhattan, with his parents and younger brother, Charlie O'Connell, who is also an actor. He is of one half Irish, one quarter Italian, and one quarter Polish, descent. Jerry began his acting career at a very young age. He did commercial work and TV work before getting the role of "Vern Tessio" in the popular film Stand by Me (1986) opposite River Phoenix and Corey Feldman. After that, he worked on several TV-Movies and TV-series and had a starring role in My Secret Identity (1988). From 1991 to 1994, Jerry attended New York University where he majored in film, but he didn't graduate.

In 1993, he starred in the film Calendar Girl (1993) opposite Jason Priestley. In 1995, he starred in the TV-movie western The Ranger, the Cook and a Hole in the Sky (1995) and, in 1996, he landed the role of "Frank Cushman" in the successful film Jerry Maguire (1996) opposite Tom Cruise. Over the next few years, he starred in Scream 2 (1997), had a small uncredited role in Can't Hardly Wait (1998), as well as appearing in several TV-movies and having starring roles in the TV-series Sliders (1995) and the film Body Shots (1999) opposite Sean Patrick Flanery and Tara Reid.

In 2000, he appeared in the Brian De Palma film Mission to Mars (2000) with Gary Sinise, among others. He has also appeared in movies such as Tomcats (2001), Buying the Cow (2002), Kangaroo Jack (2003), Yours, Mine & Ours (2005), Man About Town (2006) and Room 6 (2006). In 2007, he married actress/model Rebecca Romijn, and they have twin girls.