He spent his entire 12-year Major League Baseball (MLB) career with the Giants, from 2009 until his retirement at the conclusion of the 2021 season.

He and Madison Bumgarner both made their Major League debuts in 2009 and established a reputation as one of the best batteries in recent MLB history.

In 2011, after he was severely injured in a collision with the Florida Marlins' Scott Cousins at home plate, Posey missed most of the year.

Posey is the second player in MLB history, after Pete Rose, to win the Rookie of the Year, a League MVP, and three World Series championships.

[4] As a sophomore, Posey moved to the catcher position on the suggestion of assistant coach Mike Martin Jr.[11] He batted .382 with three home runs and 65 RBI.

[13][14] On May 12, he hit a grand slam and played all nine fielding positions in a 10–0 victory over Savannah State University; as a pitcher that day, he struck out both batters he faced.

[30] On July 13, Posey was promoted to the Giants' Class AAA team, the Fresno Grizzlies of the Pacific Coast League.

[30] Because of an injury to Giants starting catcher Bengie Molina, Posey was called up to MLB for the first time on September 2, 2009.

[32] On September 11, 2009, Posey made his MLB debut, striking out in his first at bat against Hiroki Kuroda of the Los Angeles Dodgers.

[40][41] Posey hit his first career grand slam against Chris Narveson of the Milwaukee Brewers on July 7, en route to a two-home run, four-hit, six-RBI night.

[42] This was part of a ten-game streak from July 1 to 10 during which he batted .514 with 19 hits, six home runs, and 13 RBI to set a National League (NL) record for rookies during any ten-day stretch according to the Elias Sports Bureau.

[44] In a July 10 game against the Washington Nationals, Posey was inserted into the Giants' batting order as the clean-up hitter, which became his regular position in the lineup.

[48] On September 21, Posey hit an eighth-inning home run against Andrew Cashner of the Chicago Cubs to win the game, 1–0.

"[59] Posey set season highs with three hits and four RBI on April 6, 2011, including a two-run home run against Tim Stauffer in an 8–4 victory over the Padres.

"[65] The collision led Major League Baseball to adopt rule 7.13, informally known as the "Buster Posey Rule",[66] which states that "a runner attempting to score may not deviate from his direct pathway to the plate in order to initiate contact with the catcher (or other player covering home plate)."

[79] As a result, Posey led both leagues in batting in 2012 with an average of .336, becoming the first catcher to lead the NL in hitting since Ernie Lombardi of the Boston Braves in 1942.

[88] He was named the NL Comeback Player of the Year,[89] and he received the Willie Mac Award from the Giants' organization.

[90] Eligible for salary arbitration for the first time, Posey signed a one-year, $8 million contract with the Giants prior to spring training in 2013.

[91] On March 29, Posey agreed to an eight-year contract extension worth $167 million, said by the Giants to be the most lucrative in franchise history.

[95] On June 25, 2014, in a 4–0 win over the San Diego Padres and playing first base, Posey caught the final out of Tim Lincecum's second career no-hitter.

In the 2014 World Series, the Giants defeated the Kansas City Royals in seven games, giving Posey his third championship in five years.

[100] On June 9, 2015, Posey caught rookie Chris Heston's no-hitter against the New York Mets at Citi Field, including the final out, a strikeout.

This put him one behind the record for no-hitters caught, held by the Philadelphia Phillies' Carlos Ruiz and the Boston Red Sox' Jason Varitek.

[107] On September 27, in a 12–3 win over the Colorado Rockies, Posey recorded the 1,000th hit of his career, a solo home run off of Germán Márquez.

While batting in the first inning in San Francisco's 2017 home opener, Posey was hit in the helmet by a 94 mph (151 km/h) pitch from Arizona Diamondbacks pitcher Taijuan Walker.

Although Posey felt OK after receiving medical attention, Giants manager Bruce Bochy removed him from the game to undergo further tests.

[118] Posey opted out of playing in the shortened 2020 season, largely due to his ongoing adoption of premature twin girls and the COVID-19 pandemic.

[122] According to ESPN Stats & Info, he joins Lou Brock, Will Clark, Roberto Clemente, David Ortiz, and Kirby Puckett as the sixth and only players to hit .300 in their final seasons in MLB's divisional play era (1969–present).

[126] Posey announced his retirement from baseball on November 4, 2021, making him just the fifth player in the San Francisco era to spend his entire career with the Giants (minimum of 10 seasons), joining Jim Davenport (1958–1970), Scott Garrelts (1982–1991), Robby Thompson (1986–1996) and former battery mate Matt Cain (2005–2017).

[169] Posey is mentioned in American rapper and Giants fan E-40's eighteenth studio album The Block Brochure: Welcome to the Soil 4.