Byrne appeared as Ellen Parsons in the legal thriller series Damages (2007–2012), which earned her two Golden Globe Awards nominations and two Primetime Emmy Award nominations. Get Him to the Greek (2010) and Bridesmaids (2011) established her as a comedic actress, in addition to the dramas and thrillers in which she continues to appear. She has since starred in a number of commercially successful comedies and dramas, including Insidious (2010) and its sequel Insidious: Chapter 2 (2013), X-Men: First Class (2011) and its sequel X-Men: Apocalypse (2016), Annie (2014), as well as Peter Rabbit (2018) and its sequel Peter Rabbit 2: The Runaway (2021). Byrne also portrayed Gloria Steinem in the miniseries Mrs. America (2020) and led the comedy series Physical (2021–2023) and Platonic (2023).
Byrne has been in relationship with American actor Bobby Cannavale since 2012 and they have two sons. And she is the sister-in-law of New Zealand actress Rose McIver from her brother's marriage.