[2] Seen as a potential early-round selection in the 2009 Major League Baseball (MLB) draft, Yastrzemski indicated that he would attend college unless chosen in the first round.

[16] After the all-star game, he was promoted to the Frederick Keys of the Class A-Advanced Carolina League, where he batted .312 in 93 at-bats.

[9][17] Between Frederick and Bowie, Yastrzemski combined to bat .288 with 14 home runs, 18 stolen bases in 24 attempts, and 18 triples, which led all of Minor League Baseball.

[16] He spent 2016 with both Bowie and the Norfolk Tides of the Class AAA International League,[19] where he posted combined statistics of a .234 batting average, with 13 home runs, and 59 RBIs.

[24] On March 22, 2019, the Orioles traded Yastrzemski to the San Francisco Giants in exchange for minor league pitcher Tyler Herb.

[26][27] The Giants promoted Yastrzemski to the Major Leagues on May 25, 2019, and he made his debut the same day, going 0-for-3 with a run scored in a 10–4 loss to the Arizona Diamondbacks.

[28] He collected his first career hit, a single, the following day but was thrown out returning to first base and went 3-for-4 with a run scored in the Giants' 6–2 loss.

[29] Yastrzemski hit his first career home run against his former organization, the Baltimore Orioles, off Andrew Cashner on May 31.

[31] On September 17, he hit his 20th home run, a solo shot to the center field bleachers, in his first game at Fenway Park, where his grandfather played his entire 23-year MLB career.

[32] The next game, in front of a Boston Red Sox crowd, Yastrzemski caught the ceremonial first pitch from his grandfather.

Yastrzemski joined Bobby Thomson and Dave Kingman as the only other Giants to hit 30 home runs so quickly in their careers.

He was 8th in voting for NL MVP and won the Willie Mac Award for being the Giants' most inspirational player.

[1][36] On June 15, 2021, at Oracle Park, in a 9–8 win over the Arizona Diamondbacks, with the Giants trailing 8–5 in the eighth inning with two outs and having earlier trailed 7–0, Yastrzemski hit his first career grand slam, a go-ahead home run off of Humberto Castellanos into McCovey Cove for a "Splash Hit".

[1] He was one of three nominees for a National League Gold Glove Award in right field,[39] losing to Adam Duvall.