In 2005, Collet-Serra was given an opportunity to direct his first feature film by Producer Joel Silver (The Matrix). The film, House of Wax, was a remake of the 1953 original of the same name. Despite reviewers giving the film a negative critical reception, it was a financial success, and starred Elisha Cuthbert and Chad Michael Murray. Two years later, Collet-Serra directed Goal II: Living the Dream. The film finds star European soccer player Santiago Muñez (Kuno Becker) bumped by his agent (Stephen Dillane) from England's Newcastle United team to Real Madrid's Galácticos. He reunited with Producer Silver for the third film of his career, Orphan, a 2009 American psychological horror film starring Vera Farmiga, Peter Sarsgaard, and Isabelle Fuhrman. The film centres on a couple who, after the death of their unborn child, adopt a mysterious nine-year-old girl. Orphan was produced by Joel Silver and Susan Downey of Dark Castle Entertainment and Leonardo DiCaprio and Jennifer Davisson Killoran of Appian Way Productions. The film received mixed critical reviews but was a box office success.

Collet-Serra then directed Unknown, a 2011 British psychological thriller starring Liam Neeson, Diane Kruger, January Jones, Aidan Quinn, Bruno Ganz, and Frank Langella. The film is based on the 2003 French novel published in English as Out of My Head, by Didier Van Cauwelaert. Collet-Serra made his television directing debut with the ABC pilot The River, a horror drama from Paranormal Activity writer-director Oren Peli. The show was met with generally favourable reviews. In December 2012, he began filming for his next film Non-Stop, which starred Liam Neeson and Julianne Moore.

Collet-Serra directed and executive produced The Shallows, a 2016 horror-thriller starring Blake Lively, from a script by Anthony Jaswinski, and The Commuter, an action-thriller starring Liam Neeson, which was released on January 12, 2018, and also features Vera Farmiga, Sam Neill, and Elizabeth McGovern.