In 1966 he joined Shin Bet, and initially trained to be a field officer working in the Arab sector. In 1972 he was appointed to a senior position in the Jerusalem, Judea and Samaria Command, and in 1975 became head of the Shin Bet's training division. In 1978 he became head of its Northern Command, before returning to the Jerusalem, Judah and Samaria Command to head it in 1981. In 1987 he became Deputy Director of the Shin Bet, before becoming Director the following year.
During his period in charge, he introduced structural changes to address problems that arose during the First Intifada, and address with the new security situation in Israel in the wake of the Oslo Accords. In 1994 he took leave to study at Harvard University, where he obtained a degree in economics and business management. The following year he retired from Shin Bet. He later went into business, and also taught at Harvard. He was CEO of Cellcom Israel from 1995 until 2003, and in 2012 he featured in a documentary film, The Gatekeepers and discussed the main events of his tenure in the Shin Bet.
He joined the new Yesh Atid party prior to the 2013 Knesset elections. He was elected to the Knesset, after which he was appointed Minister of Science, Technology and Space. He was placed fifth on the party's list for the 2015 elections, and was re-elected as the party won 11 seats.
Peri is a fluent Arabic speaker, having learned both in school and during his Shin Bet service.