Wisse was born in Czernowitz in what is today Ukraine, but was then part of Romania. She grew up in Montreal, Canada and earned her PhD from McGill University in 1969. As a professor, Wisse has previously taught at McGill, Stanford, New York, Hebrew and Tel Aviv universities. While teaching at McGill, she developed a "pioneering" graduate program in Jewish studies."

She received one of the 2007 National Humanities Medals. The award cited her for "scholarship and teaching that have illuminated Jewish literary traditions. Her insightful writings have enriched our understanding of Yiddish literature and Jewish culture in the modern world."

According to one critic, Wisse's work has been characterized "by the sharpness of her insight, by her unwillingness to retreat from a skirmish and by the inability of even those who disagree with her to deny her brilliance." Noam Chomsky, on the other hand, was appalled by her remark in Commentary in 1988 that "Palestinian Arabs [are] people who breed and bleed and advertise their misery."

She is a member of the Editorial Board of the Jewish Review of Books and a frequent contributor to Commentary. She dedicated her last book, Jews and Power, to the editor, Neal Kozodoy.