Over the 154 years of Major League Baseball history, and over 238,500 games played, there have been 24 official perfect games by the current definition. No pitcher has thrown more than one. The perfect game thrown by Don Larsen in Game 5 of the 1956 World Series is the only postseason perfect game in major league history and one of only three postseason no-hitters. The first two major league perfect games, and the only two of the premodern era, were thrown in 1880, five days apart. The frequency of perfect games has significantly increased since 1981. Fifteen perfect games were thrown in the 44 seasons from 1980 through 2023, while only nine were thrown in the 100-plus prior seasons. There were three perfect games in 2012; the only other year of the modern era in which as many as two were thrown was 2010. By contrast, there have been spans of 23 and 33 consecutive seasons in which no perfect game was thrown. Though two perfect-game bids have gone into extra innings, no extra-inning game has been completed to perfection.

The first two perfect games occurred under rules that differed in many important respects from those of today's game: in 1880, for example, only underhand pitching—from a flat, marked-out box 45 feet from home plate—was allowed, it took eight balls to draw a walk, and a batter was not awarded first base if hit by a pitch. Lee Richmond, a left-handed pitcher for the Worcester Ruby Legs, threw the first perfect game. He played professional baseball for six years and pitched full-time for only three, finishing with a losing record. The second perfect game was thrown by John Montgomery Ward for the Providence Grays. Ward, a decent pitcher who became an excellent position player, went on to be inducted into the Baseball Hall of Fame.

Though convention has it that the modern era of Major League Baseball begins in 1900, the essential rules of the modern game were in place by the 1893 season. That year the pitching distance was moved back to 60 feet, 6 inches, where it remains, and the pitcher's box was replaced by a rubber slab against which the pitcher was required to place his rear foot. Two other changes in crucial rules had been made in years shortly before that: In 1887, the rule awarding a hit batsman first base was instituted in the National League (this had been the rule in the American Association since 1884: first by the umpire's judgment of the impact; as of the following year, virtually automatically) and in 1889, the number of balls required for a walk was reduced to four. Thus, from 1893 on, perfect games occurred under fundamental rules identical to today, with four significant exceptions: counting a foul ball as a first or second strike, enforced by the National League as of 1901 and by the American League two years later; the use of the designated hitter in American League games (and interleague games played with the American League team as the home team) since the 1973 season and National League games starting with the 2022 season; the tiebreaker rule of a runner on second starting with the tenth inning in 2020; and the use of the pitch clock and batter clock starting in 2023.

During baseball's modern era, 22 pitchers have thrown perfect games. Most were accomplished major leaguers. Seven have been inducted into the Baseball Hall of Fame: Cy Young, Addie Joss, Jim Bunning, Sandy Koufax, Catfish Hunter, Randy Johnson, and Roy Halladay.

David Cone won the Cy Young Award once, pitched a 19-strikeout game, was part of five World Series winning teams, and was named to five All-Star teams. Félix Hernández is likewise a one-time Cy Young winner, as well as a six-time All-Star. Four other perfect-game throwers, Dennis Martínez, Kenny Rogers, David Wells and Mark Buehrle, each won over 200 major league games.

Others include Matt Cain, a three-time All-Star, who pitched well in the postseason for two World Series–winning Giants teams. Mike Witt was a two-time All-Star who finished 3rd for the 1986 Cy Young Award, going 117–116. Tom Browning was a one-time All-Star with a career record of 123–90, and pitched for the 1990 World Series winning Cincinnati Reds.

Don Larsen, Charlie Robertson, and Len Barker were journeyman pitchers—each finished his major-league career with a losing record; Barker made one All-Star team, Larsen none (Robertson played his entire career before the establishment of the MLB All-Star Game).

Dallas Braden retired with a 26–36 record after five seasons due to a shoulder injury. Philip Humber's perfect game was the only complete game he recorded, and his major league career, in which he went 16–23, ended the year after he threw it. Domingo German threw his perfect game following a start in which he allowed 10 runs in 3 and one-third innings.