Born in Birmingham, Alabama, to a family of immigrants from Sweden, "Freij" had four children, his second marriage being to an Iranian-Assyrian scholar, Eden Naby, from Urmia, Iran who teaches at Columbia University. He spoke fluent Russian, German, Arabic, Persian, Pashto, French, Uzbek, and Turkish, and had extensive knowledge of Avestan, Pahlavi, Sogdian, and other Iranian languages and dialects, both extinct and current.
Although Frye is mostly known for his works about Iran, the Iranian peoples and Iranian Central Asia, the scope of his studies was much wider and includes Byzantine, Caucasian, and Ottoman history, Eastern Turkistan, Assyria and the Assyrian people, ancient and medieval Iranian art, Islamic art, Sufism, Chinese and Japanese archeology, and a variety of Iranian and non-Iranian languages including Avestan, Old Persian, Middle Persian, Parthian, Sogdian, Khotanese, and Bactrian, New Persian, Arabic, Turkish, and even Chinese, beside research languages which include French, German, Italian, and Russian.
Frye was born in Birmingham, Alabama. He first attended the University of Illinois, where he received a BA in history and philosophy in 1939. He received his MA from Harvard University in 1940 and his PhD from Harvard in 1946, in Asiatic history.
Frye served with the Office of Strategic Services during World War II. He was stationed in Afghanistan and traveled extensively in the Middle East, Central Asia, and South Asia. In 1948 he visited Sar Masshad, and was the first European to find and report the existence of the Gur-e Dokhtar tomb (meaning "Tomb of the Maiden" in Persian).
He returned to Harvard to teach. He was a member of the Harvard faculty from 1948 until 1990. He then became a professor emeritus at Harvard.
Professor Frye helped found the Center for Middle Eastern Studies at Harvard, the first Iranian studies program in America. He also served as Director of the Asia Institute in Shiraz (1970–1975), was on the Board of Trustees of the Pahlavi University at Shiraz (1974–78), and Chairman, Committee on Inner Asian Studies, at Harvard (1983–89), and as Editor of the Bulletin of the Asia Institute (1970–1975 and 1987–99).
Among Frye's students were Annemarie Schimmel, Oleg Grabar, Frank Huddle (former US Ambassador to Tajikistan), John Limbert, and Michael Crichton, whose Hollywood film The 13th Warrior is loosely based on Frye's translation of Ibn Fadlan's account of his travels up the river Volga.
Frye was also directly responsible for inviting Iranian scholars as distinguished visiting fellows to Harvard University, under a fellowship program initiated by Henry Kissinger. Examples of such guests include Mehdi Haeri Yazdi (1923–1999), Sadegh Choubak, Jalal al Ahmad, and others.