Hoffmann received his D.Phil. from the University of Oxford, submitting his thesis on the heretic Marcion in 1982. He served during the 1980s as an assistant professor at the University of Michigan. In 1990, he was a professor of humanities at California State University. He also taught at the American University of Beirut, Westminster College in Oxford, and Africa University in Zimbabwe. He later became a visiting professor of religion at Wells College, where he was appointed to a tenure-track position by 2005.
Hoffmann is chairman of the Committee for the Scientific Examination of Religion, and was senior vice president of its parent organisation, the Center for Inquiry. He contributed a commentary article to Free Inquiry magazine to accompany their reprints of the controversial Jyllands-Posten Muhammad cartoons in 2006. When Borders bookstores decided not to stock that issue of the magazine, he wrote an article unfavourably contrasting the chain's unwillingness to take a risk with the attitude of its original store in Ann Arbor, which he had visited while teaching at Michigan during the 1980s. Later that year he took the contra position toward the existence of God in a debate at Florida State University with Richard Swinburne, formerly the Nolloth Professor of Philosophy of the Christian Religion at Oxford.
Hoffmann welcomed the attention drawn to debates about early Christianity by the documentary film The Lost Tomb of Jesus (2007), but rejected the filmmakers' conclusion that the Talpiot Tomb was the burial place of Jesus and his family. He drew online attention with an open letter alleging that Harvard University's Humanist Chaplain Greg Epstein was promoting "Gen-X humanism" and abusing his link to Harvard for publicity purposes, after Epstein had criticised the work of atheist authors Sam Harris and Richard Dawkins.
Hoffmann's 1982 doctoral thesis, Marcion: On the Restitution of Christianity, was published in 1984. His assessment that Marcion must be dated substantially before the dates assigned on the basis of patristic testimony bore significant implications for the dating of the New Testament canon and the origins of the gospel traditions. According to Hoffmann, Marcion possessed the earliest version of Luke and preserved the primitive version of Paul's letters.
Reviews of the Marcion reflected the controversial nature of the work. J. L. Houlden commended Hoffmann's skill in "reading between the lines" of Marcion's ancient critics and called the book "a model of how doctrinal history should now be written", while George E. Saint-Laurent concluded, "[H]ereafter Marcion's positive contribution to the mainstream tradition of Catholic-Orthodox Christianity so far as the decisive role of Paul is concerned will have to be acknowledged. Other reviewers thought that Hoffmann's examination of the evidence was valuable but that his conclusions could only be regarded as speculative. The book received a very negative assessment from C. P. Bammel, who accused the author of numerous historical errors and misinterpretations of patristic texts. In a book published in 1993, Bart D. Ehrman wrote that Hoffmann's Marcion had "not been well received".
Hoffmann responded to critics of the Marcion in a special issue of The Second Century. His thesis has since been revisited by New Testament scholars including David Trobisch and Joseph Tyson.
Hoffmann has also produced reconstructions in English of several pagan opponents of Christianity: Celsus (1987), Porphyry (1994) and Julian the Apostate (2004). Reviews of the Celsus were mixed with one critic suggesting that the translation improved Celsus' arguments.
The Porphyry contained a new translation of the fragments of an unknown pagan critic of Christianity preserved by the writer Macarius Magnes, previously translated into English by W. Crafer. The argument that the pagan critic was Porphyry was first advanced by the historian Adolph von Harnack.