Quayle was born in Indianapolis, Indiana, to Martha Corinne (nee Pulliam) and James Cline Quayle. He has sometimes been incorrectly referred to as James Danforth Quayle III. In his memoirs, he points out that his birth name was simply James Danforth Quayle. The name Quayle originates from the Isle of Man, where his great-grandfather was born.

Quayle became an investigator for the Consumer Protection Division of the Office of the Indiana Attorney General in July 1971. Later that year, he became an administrative assistant to Governor Edgar Whitcomb. From 1973 to 1974, he was the Director of the Inheritance Tax Division of the Indiana Department of Revenue. Upon receiving his law degree, Quayle worked as associate publisher of his family's newspaper, the Huntington Herald-Press. In 1976, Quayle was elected to the House of Representatives from Indiana's 4th congressional district, defeating eight-term incumbent Democrat J. Edward Roush by a 55%-to-45% margin. He won reelection in 1978 by the greatest percentage margin achieved to date in that northeast Indiana district. In 1980, at age 33, Quayle became the youngest person ever elected to the Senate from the state of Indiana, defeating three-term incumbent Democrat Birch Bayh by taking 54% of the votes to Bayh's 46%. Making Indiana political history again, Quayle was re-elected to the Senate in 1986 with the largest margin ever achieved to that date by a candidate in a statewide Indiana race, taking 61% of the vote and defeating his Democratic opponent, Jill Long. In November 1978, Quayle was invited by Congressman Leo Ryan of California to accompany him on a delegation to investigate unsafe conditions at the Jonestown settlement in Guyana, but Quayle was unable to participate. The decision likely saved Quayle's life, because Ryan and his entourage were subsequently murdered at the airstrip in Jonestown as the party tried to escape the massacre. In 1986, Quayle was criticized for championing the cause of Daniel Anthony Manion, a candidate for a federal appellate judgeship, who was in law school one year above Quayle. The American Bar Association had evaluated Manion as "qualified/unqualified", its lower passing grade. Manion was nominated for the Seventh Circuit of the U.S. Court of Appeals by President Ronald Reagan on February 21, 1986, and confirmed by the Senate on June 26, 1986.

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