His illustrations have appeared on the covers and interior pages of magazines such as Time, Rolling Stone, GQ, Esquire, National Geographic, Der Spiegel, and others.
[6] Later influences for O'Brien include various contemporary artists such as Gottfried Helnwein, George Tooker and Mark Tansey, as well as illustrators such as Guy Billout and David Suter.
[7] O'Brien credits his first big break as a Time magazine cover done in 1989,[2] painting a small teardrop overlaid on a Gilbert Stuart portrait of George Washington.
[14] O'Brien's "The End of Bin Laden" cover, which the artist created in 2002 when editors at Time believed the al-Qaeda leader was trapped and was or would soon be dead in Afghanistan,[5] was not published until nine years later in the May 20, 2011, issue.
[2][15] O'Brien used a similar approach for an earlier Time cover, "The Death of Abu Mousab al-Zarqawi",[16] for the June 19, 2006, issue of the magazine.
[29] In 2012, O'Brien said the work he was most proud of was his 2008 cover illustration for Rolling Stone in which the magazine endorsed candidate Barack Obama for president.
[11] The cover, which depicted the future president with a halo-like glow around him, created a mild controversy, with critics of the image saying it deified the candidate.
[36] For the cover that went to newsstands, titled Sugar Kills, O'Brien created a surreal vignette of a glass pitcher as a human skull.
[48][49][50] O'Brien also designed postage stamps of Judy Garland in 2006;[51] Danny Thomas in 2012;[52] Shirley Temple in 2016;[53] and Father Theodore Hesburgh in 2017.
[54] On April 26, 2016, O'Brien spoke at the United Nations in New York City at the invitation of the World Intellectual Property Organization, during which his artwork was shown.
[4] Since 2006, O'Brien has run the New York City Marathon, raising money for the Children's IBD Center at Mount Sinai Hospital.