Killebrew was an All-State quarterback at Payette High School when Washington Senators scout Ossie Bluege saw him playing in an impromptu baseball game. After seeing Killebrew's raw power, Bluege reported back to the Senators who immediately signed him up to a $30,000 contract. Because of his large bonus, Killebrew was a bonus baby. Because of the Bonus Rule, he was immediately added to the big league roster in 1954 at the age of 18. He played only small parts for five seasons, bouncing back and forth between the Double A Chattanooga Lookouts and Washington. While Killebrew was in Chattanooga, he became the only person to hit a homerun over the 471-foot deep centerfield wall at Engel Stadium. Finally he made it into the lineup regularly in 1959, hitting 42 homers. The Senators moved to Minneapolis, Minnesota to become the Minnesota Twins in 1961.

Killebrew was a stocky 5 ft 11 in, 210 pounds (95 kg) hitter with a short, compact swing that generated tremendous power. Killebrew became one of the American League's most feared power hitters of the 1960s, belting 40 homers in a season eight times. In 1965 he helped the Twins reach the World Series where they lost to the Los Angeles Dodgers. Killebrew had his finest season in 1969, hitting 49 home runs, driving in 140 RBI's, and winning the MVP Award. Killebrew led the league in home runs six times, in RBI three times, and was named to eleven All Star teams. As a result, he was nicknamed "Killer" - a portmanteau linking the first 5 letters of his last name with his legendary hitting ability.

On June 3, 1967, Killebrew blasted the longest home run ever hit at the Twins' old park, Metropolitan Stadium, a shot that landed in the second deck of the bleachers, and 4 years later on August 10, 1971, he hit his 500th career home run, at Metropolitan Stadium.

Despite his "Killer" nickname and his powerful style of play, Killebrew was in fact a quiet, kind man who was not much given to the partying lifestyle enjoyed by his peers. Asked once what he liked to do for fun, Killebrew replied, "Well, I like to wash dishes, I guess."

Injuries reduced his effectiveness in the early 1970s, and after a one-year stint with the Kansas City Royals he chose to retire. Killebrew hit 573 home runs in his career (eighth best all time, most by an American League right-hander, and second in the AL only to Babe Ruth, as of 2005) and drove in 1,584 runs. He was elected to the Baseball Hall of Fame in 1984, the first Minnesota Twin to be so honored. The street along the south side of the enormous Mall of America, the former site of the Metropolitan Stadium ("The Met"), has been named "Killebrew Drive" in honor of Harmon Killebrew. His uniform number 3 was the first to be retired by the Twins, and is only one of five Twins to have their jersey retired - Tony Oliva, Rod Carew, Kent Hrbek and Kirby Puckett are the others. He is, by a wide margin, the all-time homerun leader among players born in the state of Idaho.

Following his retirement, Killebrew became a successful entrepreneur in insurance, financial planning, and car sales. In 1990 he retired from business to pursue endorsement and charity work, especially in the fields of preventive and palliative health care charities and causes. Killebrew currently resides in Scottsdale, Arizona

In 1999, he ranked Number 69 on The Sporting News' list of the 100 Greatest Baseball Players, and was nominated as a finalist for the Major League Baseball All-Century Team.

Common Folklore suggests that the silhouette of Harmon Killebrew swinging a bat is the official logo of Major League Baseball. However, MLB.com states the following:

"The MLB logo: No one player has ever been identified as the model of the 1969 Major League Baseball batter logo".