In 2011, Skarsgård was nominated for a Guldbagge Award for his leading role as Simon in Simple Simon. At the age of 21, he won the European Film Academy's Shooting Stars Award in 2012. Beginning in 2013, Skarsgård played the role of Roman Godfrey in the Netflix original Hemlock Grove.
In April 2014, Skarsgård featured on the cover of Hero – a bi-annual men's fashion and culture magazine, shot by Hedi Slimane. In the issue, he is interviewed by his father.
Skarsgård played Matthew in the science fiction thriller The Divergent Series: Allegiant (2016), his first major American film. He played horror villain Pennywise the Dancing Clown in the 2017 film It and reprised the role in the 2019 sequel. His role was met with praise from fans and critics alike.
In 2022 Skarsgård played Clark Olofsson the notorious Swedish criminal whose involvement in the Norrmalmstorg robbery gave rise to the term Stockholm syndrome. The 6 part Netflix series features Skarsgård in the lead role. Of his character Bill said "This guy was basically famous his entire life for doing everything wrong, and I don't know what it says about our culture at that time or even our culture today..."
Skarsgård was a series regular on 2018's Castle Rock, as a young man with an unusual legal problem. That same year, he portrayed Zeitgeist in Deadpool 2. In 2020, he played Mateo in episode 4 of AMC's anthology series Soulmates.
Skarsgård is in a relationship with Alida Morberg. In October 2018, their daughter was born.