Subsequent credits include Herbie: Fully Loaded (2005), Zodiac (2007), Date Night (2010), Abraham Lincoln: Vampire Hunter (2012), White House Down (2013), Under the Silver Lake (2018), and Unhinged (2020).

This was followed by a supporting role in the Stephen King miniseries Rose Red in 2002, and appearances on television shows such as 24, NYPD Blue, Cold Case, Carnivàle, and It's Always Sunny in Philadelphia, where he played the recurring character Liam McPoyle over several seasons, beginning in 2005.

[5] Film credits during this period included the sports comedy Herbie: Fully Loaded (2005), the revisionist Western Seraphim Falls (2006), and the critically acclaimed David Fincher thriller Zodiac (2007).

[11][12] Simpson's next projects were the films Abraham Lincoln: Vampire Hunter (2012), The Truth About Emanuel (2013), Knights of Badassdom (2013), and the Roland Emmerich action thriller White House Down (2013), where he played a villainous computer hacker.

Den of Geek felt he displayed a "raw, manic energy" in his portrayal of Soldier—a psychotic drug dealer—that was "by turns infectious and terrifying", adding, "Seriously, [Simpson] is such a great bad guy".

His portrayal of William, a businessman who visits the titular Wild West-themed amusement park and falls in love with one of its android inhabitants, was described as "spellbinding" by Maureen Ryan of Variety.

[22] In 2017, Simpson appeared as Walton, a lieutenant aboard the titular spaceship ("USS Callister") in the opening episode of the fourth season of British anthology sci-fi series Black Mirror.

[24] Simpson starred as the real-life Russell Poole in Unsolved, a ten-part miniseries based on the 1990s murders of rappers Tupac Shakur and Biggie Smalls, which ran on the USA Network between February and May 2018.

[26]Simpson's next roles were in David Robert Mitchell's neo-noir black comedy Under the Silver Lake (2018), the action thriller Unhinged (2020), and the comedic crime drama Breaking News in Yuba County (2021).

He also headlined the ten-part Epix series Perpetual Grace, LTD in 2019, earning strong reviews for his portrayal of James Schaeler,[27] an ex-firefighter embroiled in a conspiracy to scam a corrupt pastor; Darren Franich of Entertainment Weekly described him as "an endearingly slippery protagonist, looking terrified, sad, amused, and exhausted all at once".

[31] Following a guest voice role—as Doctor Royce Hemlock—in four episodes of the Disney+ animated series Star Wars: The Bad Batch,[32] Simpson received positive notices for his portrayal of an alcoholic father in the 2023 coming-of-age film The Starling Girl,[33][34][35] an independent drama about fundamentalist Christianity that Peter Debruge of Variety felt was "refreshing" and "rigorously realistic".