McDowell was born in Los Angeles to English actor Malcolm McDowell and American actress Mary Steenburgen. He has an older sister named Lilly (born January 22, 1981) and three younger half-brothers from his father’s marriage to Kelley Kuhr. His stepfather is actor Ted Danson, who married his mother in 1995. Since 2014, McDowell has had a running joke at his mother Mary’s expense, claiming on numerous occasions on social media that his mother is actually actress Andie MacDowell. As of 2019, Charlie is dating actress Lily Collins, the daughter of English drummer and singer Phil Collins. In September 2020, they announced their engagement.

In 2011, McDowell’s Twitter feed, @charliemcdowell, was described by Time as “one of the most hilarious Twitter feeds out there,” and in 2013 Three Rivers Press published McDowell’s book, Dear Girls Above Me, based on his Twitter feed.

His debut film, The One I Love, starring Mark Duplass and Elisabeth Moss had its world premiere at the Sundance Film Festival in January 2014, where shortly after it was acquired by RADiUS-TWC and released in August 2014. In 2015, McDowell directed Sarah Silverman’s untitled HBO series pilot. The project wasn’t picked up by the network. McDowell’s next film, The Discovery, starred Rooney Mara, Jason Segel, and Robert Redford. The film premiered at the Sundance Film Festival and was acquired by Netflix for a global release in 2017.

In March 2017, filmmaker McDowell announced he was adapting author Don DeLillo’s novel Zero K as a limited series for FX with Noah Hawley and Scott Rudin producing. McDowell previously directed an episode of Hawley’s TV series Legion, also for FX.

In 2019, McDowell directed the first and last episodes of the Showtime series On Becoming a God in Central Florida and also served as an executive producer. He also directed episodes of Silicon Valley, Dear White People, Tales from the Loop and Dispatches from Elsewhere.