Nguyen has worked on such titles as Jet with Dan Abnett, Wildcats v3.0 with Joe Casey, Batman with Judd Winick, Manifest Eternity with Scott Lobdell, and the latest revamp of The Authority, The Authority: Revolution, with Ed Brubaker. He was also the artist on a six-issue arc of Superman/Batman entitled "Torment", written by Alan Burnett.
Starting with issue #840, Nguyen became the regular ongoing artist on one of DC's flagship titles, Detective Comics, with writer Paul Dini. Their run lasted until issue #852, after which the pair launched Batman: Streets of Gotham, which lasted 21 issues and was canceled in March 2011. In 2012, Nguyen collaborated with writer Scott Snyder on the miniseries American Vampire: Lord of Nightmares, which made the New York Times Best Seller list in 2013. He subsequently launched Batman: Li'l Gotham with co-writer Derek Fridolfs, an all ages series that was positively reviewed by Brian Truitt of USA Today. In rendering that series, Nguyen drew inspiration from the cartoons of the 1980s and '90s that he viewed in his childhood, explaining that in watching them, "you get this goofy view of the world."
In 2015, Jeff Lemire launched his creator-owned Image Comics series, Descender, with Nguyen as artist, for which Nguyen won the 2016 and 2019 Eisner Award for Best Painter/Multimedia Artist.