In addition to writing or co-writing the screenplays for feature or short films that he directed such as Shards (2004) (short), Love Bytes (2005)(documentary short), The Wackness (2008), Warm Bodies (2013), The Night Before (2015), Levine has also written an episode of the TV series The Screen Junkies Show entitled "Zombie Acting Tips" (2013). He also wrote the screenplay for the short film The Weight (2009), directed by Nicholas Jarecki (writer and Director of the film Arbitrage).

Levine's feature directorial debut was the 2006 dramatic horror film All the Boys Love Mandy Lane, starring Amber Heard with the screenplay written by Jacob Forman. The film had its premiere at the 2006 Toronto International Film Festival, followed by screenings at the Sitges Film Festival, South by Southwest, London FrightFest Film Festival, and the IFI Horrorthon, at the French Cinemathèque.

In 2008, Levine wrote and directed The Wackness, starring Josh Peck. It won the Audience Award at the 2008 Sundance Film Festival and was nominated for the Grand Jury Prize (Dramatic) as well. The Wackness also won Best Narrative Feature at the 2008 Los Angeles Film Festival, The Most Popular Feature Film Award at the 2008 Melbourne International Film Festival, and was nominated for a Best First Screenplay award at the 2008 Independent Spirit Awards. In addition, the film won Best International Feature Film at the 2008 Zurich Film Festival.

Levine filmed a pilot for a Showtime comedy series created by executive Producer Jim Carrey titled I'm Dying Up Here, based in part on the 2010 non-fiction book of the same name by william Knoedelseder about the stand-up comedy scene in LA during the 1970s.

Next, Levine directed the 2011 film 50/50 starring Seth Rogen, Joseph Gordon-Levitt and Anna Kendrick. Adam, played by Gordon-Levitt, has a highly organized and healthy lifestyle. He maintains his life in perfect control when he learns the pain in his back is from a cancerous tumor that must be removed by a complicated surgery. Adam's world has turned upside-down, but he receives strong support from his best friend, played by Seth Rogen as well as comfort from his hospital Psychiatrist and Future love interest, played by Anna Kendrick. 50/50 won the Audience Award at the 2011 Aspen Filmfest, the Audience Award at the 2011 Stockholm Film Festival and the Achille Valdata Award at the 2011 Torino International Film Festival /Torino International Festival of Young Cinema.

It has been announced that Levine will direct Brooklyn Castle, a feature film adaptation of the 2012 documentary Brooklyn Castle. The storyline tells about a group of New York's inner city, junior high school kids who wanted to compete in a highly prestigious, highly selective national chess tournament (the United States Chess Federation's National High School Championship)

In 2013, Levine directed the film Warm Bodies, starring Nicholas Hoult as a zombie who is slowly able to regain his health and humanity and return to normal life. During his change from zombie to human, he forces a girl, played by Teresa Palmer, to stay with him. The film is based on the novel of the same name by Writer Isaac Marion.

Levine also served as an executive Producer on the 2014 medical drama TV series he created for the USA Network, Rush.

In 2015, Levine directed and co-wrote the Christmas comedy film, The Night Before starring Seth Rogen, Joseph Gordon-Levitt and Anthony Mackie. (Re-teaming with Gordon-Levitt and Rogen from 50/50. Lead actors included Lizzy Caplan, Mindy Kaling, Jillian Bell and a cameo by Miley Cyrus.

Levine produced the 2016 film Mike and Dave Need Wedding Dates, directed by Jake Szymanski and starring Zac Efron, Adam Devine, Anna Kendrick, and Aubrey Plaza.