In January 2016, it was reported that Whittle was in talks for the lead role on another series. During an interview with AfterBuzz TV in April 2016, Whittle announced his decision to leave The 100. Whittle controversially accused the show's creator Jason Rothenberg of bullying him into leaving the series by marginalizing his character. The actor explained that once Warner Bros. Television President Peter Roth and The CW President Mark Pedowitz were made aware of the situation, he was allowed to audition for other projects.
In January 2016, it was announced that Whittle had been cast as Shadow Moon, the lead role in Starz television adaptation of Neil Gaiman's 2001 novel American Gods opposite Ian McShane. Though Whittle had no prior knowledge of the novel, he was a fan favourite pick to play Shadow when Starz announced the series in August 2015. Out of the 2,000 audition tapes submitted, Whittle was chosen out of approximately 600 actors that met with the producers. Whittle submitted 16 audition tapes over the five-month process. In September 2017 Whittle was cast opposite Sanaa Lathan in the Netflix original film, Nappily Ever After based on the novel of same name by Trisha R. Thomas. On April 16, 2018, it was announced that Whittle signed with talent agency William Morris Endeavor.