After working as a professional musician, reporter, and high-school English teacher, O'Brien served as a Peace Corps Volunteer in the Solomon Islands. In 1989, he entered the doctoral program in English Language and Literature at the University of Chicago, where he studied with the Renaissance scholars Janel Mueller, Michael Murrin, David Bevington, and Richard Strier. During his time at Chicago, O'Brien was awarded a MacLeish Scholarship, a Humanities Fellowship, and an Andrew W. Mellon Fellowship. He received his Ph.D. from Chicago in 1992 and began teaching at California State University, Chico. He has also taught in CSUC's London Semester program, in the Semester at Sea program, at a Buddhist temple school in Thailand, and as a Fulbright Scholar at Eötvös József College and Eötvös Loránd University in Budapest.
In 2005, O'Brien developed a Shakespeare film course that was redesigned in 2011 to be part of CSUC's new General Education program. Over one hundred students take the course each semester.