Howard Baker began his political career in 1964, when he lost to the liberal Democrat Ross Bass in a U.S. Senate election to fill the unexpired term of the late Senator Estes Kefauver. In the 1966 U.S. Senate election for Tennessee, Bass lost the Democratic primary to former Governor Frank G. Clement, and Baker handily won his Republican primary race over Kenneth Roberts, 112,617 (75.7 percent) to 36,043 (24.2 percent). Baker won the general election, capitalizing on Clement’s failure to energize the Democratic base, including specifically organized labor. He won by a somewhat larger-than-expected margin of 55.7 percent to Clement’s 44.2 percent. Baker thus became the first Republican senator from Tennessee since Reconstruction and the first Republican to be popularly elected to the Senate from Tennessee. Harry W. Wellford, then a private attorney but later a U.S. District Court justice and then U.S. 6th Circuit Court of Appeals Justice, served as Baker’s campaign chair and closest confidant. Howard Baker was re-elected in 1972 and again in 1978, serving altogether from January 3, 1967, to January 3, 1985. In 1969, he was already a candidate for the Minority Leadership position that opened up with the death of his father-in-law, Everett Dirksen, but Baker was defeated 19–24 by Hugh Scott. At the beginning of the following Congress in 1971, Baker ran again, losing to Scott this time 20–24. In 1971, President Richard Nixon asked Baker to fill one of the two empty seats on the U.S. Supreme Court. When Baker took too long to decide whether he wanted the appointment, Nixon changed his mind and nominated William Rehnquist instead.

In 1973 and 1974, Howard Baker was also the influential ranking minority member of the Senate committee, chaired by Senator Sam Ervin, that investigated the Watergate scandal. Baker is famous for having asked aloud, “What did the President know and when did he know it?” The question is sometimes attributed to being given to him by his counsel and former campaign manager, future U.S. Senator Fred Thompson. When Hugh Scott retired, Baker was elected senate minority leader in 1977 by his Republican colleagues, defeating Robert Griffin 19-18. Baker served two terms as Senate Minority Leader (1977–1981) and two terms as Senate Majority Leader (1981–1985). Howard Baker was frequently mentioned by insiders as a possible nominee for Vice President of the United States on a ticket headed by incumbent President Gerald Ford in 1976 and according to many sources, he was a frontrunner for this post. Ford, however, in a surprising move, chose Kansas Senator Bob Dole. Howard Baker ran for U.S. President in 1980, dropping out of the race for the Republican nomination after losing the Iowa caucuses to George H.W. Bush and the New Hampshire primary to Ronald Reagan, even though a Gallup poll had him in second place in the presidential race, at eighteen percent behind Reagan at 41 percent, as late as November 1979. When Baker helped Jimmy Carter pass the Panama Canal Treaties in 1978, it was overwhelmingly opposed by the public, especially Republicans. It cost him politically when he ran for president two years later, and it was a factor in why Reagan picked George H.W. Bush instead of Baker as his running mate.

Howard Baker was married to the daughters of two prominent Republicans. Baker’s first wife, Joy, who died of cancer, was the daughter of former Senate Minority Leader Everett Dirksen. In 1996, he married former U.S. Senator Nancy Landon Kassebaum, daughter of the late Kansas Governor Alfred M. Landon, who was the Republican nominee for President in 1936. Baker died on June 26, 2014, at the age of 88 from complications of a stroke he suffered the week prior. He died in his native Huntsville, Tennessee, with his wife, Nancy, by his side. Baker was a Presbyterian.