In the U.S. House, O'Neill became a protégé of fellow Boston Representative John William McCormack. O'Neill broke with President Lyndon B. Johnson on the Vietnam War in 1967 and called for Richard Nixon's resignation in light of the Watergate scandal. He quickly moved up the leadership ranks in the 1970s, becoming House Majority Whip in 1971, House Majority Leader in 1973, and Speaker of the House in 1977. With the election of President Jimmy Carter, O'Neill hoped to establish a universal health care system and a guaranteed jobs program. However, relations between Carter and Congress deteriorated, and Carter lost re-election in the 1980 presidential election to Ronald Reagan, a conservative Republican. O'Neill became a leading opponent of President Reagan's conservative domestic policies, but O'Neill and Reagan found common ground in foreign policy, fostering the Anglo-Irish Agreement and implementing the Reagan Doctrine (despite considerable opposition to Reagan's support for the Contras in Nicaragua) in the Soviet–Afghan War.
O'Neill retired from Congress in 1987 but remained active in public life. He published a best-selling autobiography and appeared in several commercials and other media. He died of cardiac arrest in 1994.