In 2019, Efron played a drug-addled libertine in the Harmony Korine film The Beach Bum, opposite star Matthew McConaughey. He also starred as serial killer Ted Bundy in Extremely Wicked, Shockingly Evil and Vile, opposite Lily Collins as Bundy's girlfriend. The film premiered at Sundance in early 2019 and was released by Netflix on May 3. Efron next voiced Fred Jones in Warner Bros.' 2020 Scooby-Doo animated film, Scoob!.
Efron announced the creation of his YouTube channel in March 2019. The video sharing platform hosts two weekly series. "Off the Grid" follows Efron and his brother Dylan as they participate in outdoor activities and trips without electronic devices—with the exception of a video camera in order to document their experiences. "Gym Time" spotlights fitness and nutrition, with Efron informing his viewers that he plans to "train with celebrities, athletes, and interesting people". YouTube received backlash for promoting Efron's new channel in a post made from their official Twitter account. Fans accused the platform of promoting a mainstream celebrity's account, which they feared would overshadow lesser known creators and would make it more difficult for them to "break through."
In December 2019, Efron contracted a serious and potentially life-threatening illness, a "form of typhoid or similar bacterial infection", while filming his adventure series Killing Zac Efron in Papua New Guinea. He was flown to St Andrews War Memorial Hospital in Australia and was treated before flying back home on Christmas Eve. He recovered without serious issue.