Trachtenberg has directed commercials for Lexus, Nike, and Coca-Cola. In 2003, he directed the short film Kickin’. In April 2008, he joined Tight Films, for which he collaborated with Matt Wolf on an alternate reality game for Hellboy II: The Golden Army.

In March 2011, Trachtenberg released a short film for BlackBoxTV titled More Than You Can Chew, starring J. Kristopher, Skye Marshall and Ian Hamrick. Trachtenberg co-wrote the story with Mark D. Walker.

On August 23, 2011, Trachtenberg released the short film Portal: No Escape, based on the video game Portal, which has garnered more than twenty-five million views.

On October 13, 2011, /Film announced that Trachtenberg would be directing a science fiction action heist film for Universal Pictures with writer Chris Morgan.

In January 2013, iFanboy broke the news that Trachtenberg would direct the film adaptation of Y: The Last Man. However, on September 25, 2014, /Film announced that the film had been cancelled.

On April 3, 2014, Ain’t It Cool News announced that Trachtenberg would direct a film for Bad Robot Productions titled Valencia, which was later revealed to be a code name for 10 Cloverfield Lane. On January 15, 2016, the trailer for 10 Cloverfield Lane was released. Producer J. J. Abrams said about the film, “The idea came up a long time ago during production. We wanted to make it a blood relative of Cloverfield. The idea was developed over time. We wanted to hold back the title for as long as possible.”

On April 30, 2018, it was announced that Dan Trachtenberg would direct the first episode of the Amazon series The Boys, replacing Seth Rogen and Evan Goldberg, who dropped out due to scheduling conflicts.

On January 14, 2019, Trachtenberg was announced to be directing a live action film adaptation of the video game series Uncharted. However on August 22, 2019, it was announced he had exited the film.