McConnell was born on February 20, 1942, to Julia Odene "Dean" (née Shockley; 1919–1993) and Addison Mitchell "A.M." McConnell II (1917–1990). McConnell was born in Sheffield, Alabama, and grew up in nearby Athens, Alabama, where his grandfather, Robert Hayes McConnell Sr., and his great uncle, Addison Mitchell McConnell, owned McConnell Funeral Home. He is of Scots-Irish and English descent. His ancestor James McConnell fought on the American side in the American Revolutionary War.

In 1950, when he was eight, McConnell moved with his family from Athens to Augusta, Georgia, where his father, who was in the Army, was stationed at Fort Gordon.

In 1956, his family moved to Louisville, Kentucky, where he attended duPont Manual High School. McConnell was elected student council president at his high school during his junior year. He graduated Omicron Delta Kappa from the University of Louisville with a B.A. in political science in 1964 with honors. He was president of the Student Council of the College of Arts and Sciences and a member of the Phi Kappa Tau fraternity.

McConnell attended the 1963 March on Washington for Jobs and Freedom, where Martin Luther King Jr. gave the "I Have a Dream" speech. In 1964, at the age of 22, he attended civil rights rallies, and interned with Senator John Sherman Cooper. He has said his time with Cooper inspired him to run for the Senate later in life.

In 1967, McConnell graduated from the University of Kentucky College of Law, where he was president of the Student Bar Association.

In March 1967, shortly before the expiration of his educational draft deferment upon graduation from law school, McConnell enlisted in the U.S. Army Reserve as a private at Louisville, Kentucky. This was a coveted position because the Reserve units were mostly kept out of combat during the Vietnam War.  His first day of training at Fort Knox, Kentucky, was July 9, 1967, two days after taking the bar exam, and his last day was August 15, 1967. Shortly after his arrival he was diagnosed with optic neuritis and deemed medically unfit for military service, and was honorably discharged. His brief time in service has repeatedly been put at issue by his political opponents during his electoral campaigns.

From 1968 to 1970, McConnell worked as chief legislative assistant to Senator Marlow Cook in Washington, D.C., managing a legislative department consisting of five members as well as assisting with speech writing and constituent services.

In 1971, McConnell returned to Louisville, where he worked for Tom Emberton's candidacy for Governor of Kentucky, which was unsuccessful. McConnell attempted to run for a seat in the state legislature but was disqualified because he did not meet the residency requirements for the office. He then went to work for a Louisville law firm, Segal, Isenberg, Sales and Stewart, for a few years. During the same time period, he taught a night class on political science at the University of Louisville.

In October 1974, McConnell returned to Washington to fill a position as Deputy Assistant Attorney General under President Gerald Ford, where he worked alongside Robert Bork, Laurence Silberman, and Antonin Scalia. He also served as acting United States Assistant Attorney General for the Office of Legislative Affairs under President Ford in 1975.

In 1977, McConnell was elected the Jefferson County judge/executive, the top political office in Jefferson County, Kentucky, at the time, defeating incumbent Democrat Todd Hollenbach, III, 53% to 47%. He was re-elected in 1981 against Jefferson County Commissioner Jim "Pop" Malone, 51% to 47%, outspending Malone 3–1, and occupied this office until his election to the U.S. Senate in 1984.

McConnell was baptized at age 8 as a Southern Baptist. He was married to his first wife, Sherrill Redmon, from 1968 to 1980 and had three daughters, Porter, Eleanor (Elly), and Claire.

McConnell's second wife, whom he married in 1993, is Elaine Chao, Secretary of Labor under President George W. Bush and Secretary of Transportation under President Donald Trump.

In February 2003, McConnell underwent a triple heart bypass surgery in relation to blocked arteries, at the National Naval Medical Center in Bethesda, Maryland.

In August 2019, McConnell suffered a fall at his Louisville home; he fractured his shoulder. In March 2023, he was hospitalized for five days after a fall; he was treated for a concussion and a minor rib fracture, and did not return to the Senate for almost six weeks. In July 2023, he fell while disembarking from a plane at Ronald Reagan Washington National Airport.

On July 26, 2023, McConnell prompted worldwide media reports when he froze, unspeaking, for around 20 seconds while addressing a press conference. He was escorted away by aides, but later returned and said he was "fine". Two days after the incident, his spokespersons said that McConnell would continue in his leadership role; he is the institution's longest-serving party leader. On August 30, 2023, he again froze during a press conference in Covington, Kentucky and was eventually led away by staff. A day later, McConnell released a letter from the attending physician of Congress that said that he was "medically clear" to continue his schedule as planned; the letter said that the physician had talked to McConnell and "conferred with his neurology team", but did not indicate that he had physically examined McConnell.