From 2010 until its ending in 2014, she starred in the HBO crime drama "Boardwalk Empire" as Margaret Thompson, the wife of Prohibition-era Atlantic City crime boss Nucky Thompson (Steve Buscemi). She appeared in all five seasons of the series. In 2011, she and the rest of the show's cast were awarded the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series. In 2016, she starred in Ricky Gervais' "Special Correspondents" as Claire Maddox, and "Swallows and Amazons" as Mrs. Walker. In 2016, she played the lead role in "Hated in the Nation", an episode of the anthology series "Black Mirror" for which she received critical acclaim. On 3 November 2016 Macdonald was featured in the trailer for Danny Boyle's "T2 Trainspotting" confirming she would reprise her role as Diane from the original film, which she did. In 2017, she co-starred opposite Benedict Cumberbatch in the BBC film "The Child in Time". Macdonald was also confirmed to be playing the guest lead in the sixth series of the BBC's Police drama "Line of Duty".