Keith Hernandez attended Capuchino High School and the College of San Mateo (also known as San Mateo Junior College).

Hernandez was drafted by the Cardinals in the 42nd round of the 1971 draft, as the 776th overall player. He quickly rose to the upper echelon in the League. In 1979, he led the league with a .344 batting average, 48 doubles, and 116 runs scored, and went on to share the National League's Most Valuable Player Award with Willie Stargell.

In 1982, the Cardinals won the World Series, defeating the Milwaukee Brewers in seven games. In Game 6, Hernandez and Cardinal catcher Darrell Porter hit home runs in a 13-1 St. Louis victory.

After several disagreements with Cardinal management, Hernandez was traded to the Mets on June 15, 1983. The Cardinals received pitchers Neil Allen and Rick Ownbey in return. While this trade was probably the best in Mets history, it was a terrible one for the Cardinals, who have not won a World Series since.

In 1985, Hernandez's cocaine use, which had been the subject of persistent rumors and the chief source of friction between Hernandez and Cards manager Whitey Herzog, became a matter of public record as a result of the Pittsburgh trial of drug dealer Curtis Strange. Hernandez made a successful recovery.

For more details on this topic, see The Pittsburgh Drug Trials.
Hernandez wore uniform number 18 for the first two years of his career. In 1976, he switched to number 37, insisting that his uniform number end with a 7 in honor of Mickey Mantle. The Mets had retired number 37 for former manager Casey Stengel, so Hernandez switched to number 17, which he wore for the remainder of his career. His arrival and veteran leadership seemed to give the Mets confidence and credibility. In 1984, his first full season with the team, the Mets improved from a record of 68-94 to 90-72. The Mets finished second behind the Chicago Cubs in 1984 and the Cardinals in 1985, but won the World Series in 1986. The following season, Hernandez was named the first team captain in franchise history.

Hernandez was often compared to New York Yankees first baseman Don Mattingly. Both had won several Gold Gloves, a batting title and a Most Valuable Player award. Unfortunately, both players also had their careers curtailed by back injuries. Hernandez also suffered from knee and hamstring problems. By 1988, at the age of just 34, Hernandez began a sharp decline, and the Mets chose not to re-sign him after his contract ran out at the close of the 1989 season.

On December 7, 1989, the Cleveland Indians signed Hernandez to a contract, but back injuries led to his appearance in only 43 games in the 1990 season. Hernandez retired after the season.

Hernandez never received enough support from the Baseball Writers Association of America (BBWAA) to be elected to the Baseball Hall of Fame. In 2004, after nine years on the ballot, he received votes from fewer than 5% of the writers, disqualifying himself for further eligibility. Hernandez may still be considered for induction by the Veterans Committee in 2011, twenty years after his retirement.