He was born in Germany in 1942.Huyssen received his doctorate from the University of Zürich in 1969, and taught at the University of Wisconsin—Milwaukee from then until 1986, when he joined the faculty at Columbia. From 1986 to 1992 and in 2005 he served as head of Columbia's Germanic Languages and Literatures department. From 1998 to 2003 he was a director of the Center for Comparative Literature and Society.

Huyssen is particularly known for his work on 18th-20th century German literature and culture, international modernism and postmodernism, Frankfurt School critical theory, cultural memory, historical trauma, urban culture, and globalization. His work has appeared in translation in Spanish, Portuguese, Turkish, Chinese, Japanese, and other languages.

He is currently working on a book project about modernist miniatures, a little studied experimental form of modernist writing, widespread in French and German modernism from Charles Baudelaire to Rainer Maria Rilke, Benn, Franz Kafka, Siegfried Kracauer, Musil, and Walter Benjamin.

In addition to his editorship of the New German Critique, Huyssen serves on the editorial boards of October, Constellations, and Germanic Review.

Married to New York Times correspondent Nina Bernstein, Huyssen is also a longtime friend of Nobel Prize-winning Turkish novelist Orhan Pamuk, and often hosts him when the writer comes to the US. The two teach an undergraduate class together at Columbia called "Words and Pictures," which examines problems of visual representation in literature, particularly theories of ekphrasis.