[6] He embarked on a long-term collaboration with Dirk Impens, originally his professor at KASK,[6] who produced all five of Van Groeningen's feature films from 2004 to 2016 under his production company Menuet.

[7] Van Groeningen made his directorial debut with Steve + Sky (2004), which depicts a romance between a drug dealer and a prostitute, and starred Titus De Voogdt and Delfine Bafort in the titular roles.

Van Groeningen later said the film "was about realizing that you're not invincible or immortal" after having an epiphany at age 23 when his father died due to complications with a liver transplant and he lost a close friend to cancer.

[13] His fourth feature film, The Broken Circle Breakdown (2012), starred Johan Heldenbergh and Veerle Baetens as Didier and Elise, a bohemian couple that loses their daughter to cancer.

[19] The film received mixed reviews from critics but was praised for the soundtrack created by the Flemish band Soulwax, who had previously collaborated with Van Groeningen on Steve + Sky.

[20] Van Groeningen made his English-language debut with the film Beautiful Boy (2018), which he directed and co-wrote, and which stars Steve Carell and Timothée Chalamet.