1976 election

Upon winning his party's Senate nomination, Sasser set out to attack the record of one-term incumbent Sen. Bill Brock, heir to a Chattanooga candy fortune. Sasser emphasized Brock's connections to former President Richard M. Nixon and his use of income tax code provisions that had, despite his great wealth and considerable income, resulted in his paying less than $2,000 in income tax the previous year. Sasser was able to capitalize on the tax issue by pointing out that Brock had paid less than many Tennesseans of considerably more modest means.

Sasser's campaign was also greatly aided by the efforts of ex-Senator Gore. Brock had defeated the elder Gore for the Senate in 1970 largely upon the basis of Gore's opposition to the Vietnam War. Sasser won handily over Brock, and went on to serve three Senate terms.

Re-election, 1982 and 1988

He turned back a serious effort against him by five-term United States Representative Robin Beard very handily in 1982. That showing was so impressive that his 1988 Republican opponent was a virtual political unknown named Bill Andersen, whose underfunded, essentially token campaign never stood a chance.

1994 re-election campaign

There were two unforeseen events that negated Sasser's popularity. Some Tennessee voters were discontented with the first two years of the Clinton administration, especially the proposal for a national health-care system largely put together and advocated by Clinton's wife, Hillary Clinton, as well as the passage of the Federal Assault Weapons Ban. The other was the somewhat unexpected nomination of Nashville heart transplant surgeon Bill Frist for the seat by the Republicans.

Frist was a political unknown and a total novice (who never voted until he was 36)^[4] at campaigning, but was from one of Nashville's most prominent and wealthiest medical families, which gave him name recognition, especially in the Nashville area, and resources adequate to match the campaign war chest built up by a typical three-term incumbent, a challenge most "insurgent" candidates find to be extremely difficult. A further factor working to Frist's advantage was a simultaneous Republican campaign by actor and attorney Fred Thompson for the other Tennessee Senate seat, which was held to replace Al Gore, who had resigned in 1993 to become Vice President of the United States. To an extent, Frist was able to bask in the reflected glory of this formidable stage presence, and additionally developed some campaigning skills, which were almost totally absent in the early stages of his campaign. Another factor in Frist's favor was that Sasser was never seen as possessing much charisma of his own. During the campaign Nashville radio stations were derisive towards Sasser to the point of stating that he could only win "a Kermit The Frog lookalike contest."^{[citation needed]} In one of the largest upsets in a night of political upsets in the November 1994 U.S. general elections, Frist defeated incumbent Sasser by approximately 14 percentage points. As of January 2024, he is the last Democrat to have represented Tennessee in the U.S. Senate.