His major anime roles include Gaara in Naruto, Naruto Shippuden, and Boruto, Vincent Law in Ergo Proxy, Captain Jushiro Ukitake in Bleach, Lloyd in Code Geass, Kenzo Tenma in Monster, Akihiko Sanada in Persona 3, and Nephrite in the Viz Media dub of Sailor Moon.

In cartoons, O'Brien has voiced characters in shows such as Star Wars Rebels, Transformers: Robots in Disguise, Avengers Assemble, Wolverine and the X-Men, and Hulk and the Agents of S.M.A.S.H..

In video games, he voiced Gollum in Middle-earth: Shadow of Mordor and its sequel, Caius Ballad in Final Fantasy XIII-2 and Lightning Returns: Final Fantasy XIII, War in Darksiders, Asura in Asura's Wrath, Ieyasu Tokugawa in Sengoku Basara: Samurai Heroes, Illidan Stormrage in World of Warcraft and Heroes of the Storm, Yasuo in League of Legends, Grimoire Weiss in Nier and Nier: Replicant ver.1.22474487139..., the Warden in For Honor, and Barker in Titanfall 2.

[4] He's of Irish ancestry[5] His mother, Lois Wiltse O'Brien, worked as an educator as well as a quality assurance trainer and consultant.

[10] He and his partner decided to leave the city in the aftermath of the September 11 attacks and pursued a voice acting career.

[10] He is also a cast member of the popular web series Critical Role, in which he and other voice actors play Dungeons & Dragons.

[21] In November 2019, Amazon Prime Video announced that they had acquired the streaming rights to this animated series, now titled The Legend of Vox Machina,[22] O'Brien reprised his role as Vax'ildan.