Tsongas (pronounced SONG-gus) was born to a working-class Greek father and native Massachusetts mother. He attended Dartmouth and Yale Law School before settling in Lowell, Massachusetts.

He first entered politics as a city councillor, elected to the Lowell City Council in 1969 and served two consecutive terms. Tsongas went on to serve as a county commissioner of Middlesex County, Massachusetts. In 1974 he was elected to the United States House of Representatives, defeating Republican incumbent Paul Cronin. He served two terms in the House, and in 1978 he was elected to the Senate, defeating incumbent Edward Brooke. In 1983, however, he was diagnosed with cancer and in 1984 announced his retirement from the Senate. After fighting the illness he returned to politics and in 1992 ran for his party's nomination for President. He ran a strong campaign and succeeded in winning the New Hampshire primary, but was eventually eclipsed by a resurgent Bill Clinton (the "Comeback Kid"), who would go on to win the Presidency. Tsongas was viewed as a centrist who embraced a number of Republican policies. He was especially known for his pro-business economic policies that have come to be embraced by many in the modern Democratic Party. In particular, he focused on the United States budget deficit and its harmful effects, a cause he continued to champion after his primary campaign ended by co-founding The Concord Coalition.

A few years later the cancer returned and he died of pneumonia and liver failure.

On January 27, 1998, the Tsongas Arena in Lowell was dedicated in his honor.