Kiner was born in Santa Rita, New Mexico. He made his major league debut on April 16, 1946 with the Pittsburgh Pirates, and his 23 home runs that season led the National League. In 1947 he gained notice for hitting 51 homers and compiling a .313 batting average. Many of Kiner's homers were hit into a short left- and left-center-field porch at Forbes Field, built for Hank Greenberg and Kiner, which became known as "Kiner's Korner".

In 1949 Kiner topped his 1947 total with 54 home runs, falling just two short of Hack Wilson's NL record. It was the highest total in the major leagues from 1939 to 1960, the highest National League total from 1931 to 1997, and made Kiner the first National League player with two fifty-home run seasons; Kiner also matched his peak of 127 runs batted in. From 1947 to 1951, Kiner topped 40 HR and 100 RBI each season. His string of seasons leading the league in home runs reached seven in 1952, when he hit 37. This was also the last of a record six consecutive seasons in which he led Major League Baseball in home runs, all under the guidance of manager Billy Meyer and hitting coach, Pirate great Honus Wagner. He was selected to participate in the All-Star Game in six straight seasons, 1948 to 1953.

On June 4, 1953, Kiner was sent to the Chicago Cubs as part of a ten-player trade. This was largely due to continued salary disputes with Pirate general manager Branch Rickey, who reportedly told Kiner, "We finished eighth with you, we can finish eighth without you." At the time, there were eight teams in the National League.

He played the rest of the 1953 season and all of 1954 with the Cubs, and finished his career with the Cleveland Indians in 1955, a back injury forcing him out of baseball at that point. At the end of his ten seasons he had amassed 369 home runs and 1019 RBI to go along with a career .279 batting average. At the time, his home run total ranked as the 6th-highest in history, trailing only the totals of Babe Ruth (714), Jimmie Foxx (534), Mel Ott (511), Lou Gehrig (493) and Ted Williams (then with 394). Kiner averaged 7.1 homers per 100 official at-bats, a frequency which then trailed only that of Ruth.

In 1961, Kiner made his way into the broadcast booth with the Chicago White Sox. The next year, Kiner, along with Lindsey Nelson and Bob Murphy started announcing the games of the expansion New York Mets on WOR-TV in New York. One of his duties was to do a post-game show known as "Kiner's Korner".

As an announcer, Kiner gained additional renown for his often unintentionally funny utterances. He was prone to mis-speaking the names of players; for instance, he called Dwight Gooden "Greg Goossen" and Darryl Strawberry "Darryl Throneberry", in each case harkening back to Mets players of the 1960s. In addition, he came up with colorful phrases such as "Two-thirds of the earth is covered by water and the other third is covered by Garry Maddox" and "If Casey Stengel were alive today, he'd be spinning in his grave."

Despite a bout with Bell's palsy, which left him with slightly slurred speech, as of 2006 Kiner is still doing Mets broadcasts. He is the only broadcaster to survive all of the Mets history, due to Nelson leaving the Mets for the San Francisco Giants in 1979 and Murphy's retirement in 2003. (Nelson died in 1995 and Murphy in 2004.) His traditional home-run call -- "it is gone, goodbye" or "that ball is gone, goodbye" -- is a signature phrase in baseball.

Kiner was inducted into the Baseball Hall of Fame in 1975, and the New York Mets Hall of Fame in 1984. The Pirates retired his uniform number 4 in 1987. The Sporting News placed him at number 90 on its 1999 list of "The 100 Greatest Baseball Players," and he was one of the 100 finalists for the Major League Baseball All-Century Team that year.