Baltimore Orioles
The Baltimore Orioles drafted Mancini in the eighth round, with the 249th overall selection, of the 2013 Major League Baseball draft. He signed, and made his professional debut with the Aberdeen IronBirds of the Low-A New York–Penn League that same year. Mancini spent the whole season with Aberdeen, batting .328 with three home runs and 35 RBI in 68 games. He began the 2014 season with the Delmarva Shorebirds of the Single-A South Atlantic League and received a midseason promotion to the Frederick Keys of the High-A Carolina League. In 137 games between the two teams, Mancini compiled a .284 batting average with ten home runs and 83 RBI. He began the 2015 season with Frederick, and was promoted during the season to the Bowie Baysox of the Double-A Eastern League. In 136 games, Mancini slashed .341/.375/.563 with 21 home runs, 89 RBI, and 43 doubles.
After spending some time in Baltimore during spring training, Mancini returned to Bowie to start the 2016 season. He was blocked at Triple-A by Joey Terdoslavich, but was nonetheless promoted to the Norfolk Tides in April as Terdoslavich struggled. He spent the remainder of the season at Norfolk, batting .280 with 13 home runs and 54 RBI in 125 games.
The Orioles promoted Mancini to the major leagues for the first time on September 18, 2016, during September call-ups. On September 20, in his major league debut as the designated hitter against the Boston Red Sox, he hit a home run against Eduardo Rodríguez in his second at-bat. His parents were in attendance to watch this, his first MLB home run. That home run made Mancini the fourth Orioles' player to hit a home run for their first Major League hit after Larry Haney (1966), Nick Markakis (2006) and Jonathan Schoop (2013). Mancini started again two nights later and hit his second career home run, a three-run homer off David Price. He became the 20th player in major league history to hit a home run in his first two starts. Mancini also became the third player in major league history to homer in their first three starts, after he hit a solo home run against the Arizona Diamondbacks on September 24.
Mancini made the Orioles' 2017 Opening Day roster after transitioning to the outfield. On April 16, 2017, Mancini recorded his second multi-home run game of the season, while driving in four runs. He tied Trevor Story and Dino Restelli for most home runs through a player's first 12 career games with seven. On April 22, Mancini hit his fifth home run of the season and eighth of his career. He tied Story and Carlos Delgado for most home runs through a player's first 17 career games. On June 7, in a game against the Pittsburgh Pirates, Mancini hit a game-tying, pinch-hit two-run home run in the ninth inning off closer Tony Watson. Two innings later, with two on and two outs, Mancini hit a walk-off three-run home run off Wade LeBlanc to give the Orioles a 9–6 victory. Per STATS, LLC, Mancini became the first Oriole to hit a pinch-hit homer in the 9th inning or later and then hit another home run in the same game. He also became the second Oriole ever to hit a game-tying home run in the 9th inning or later and then hit a walk-off homer in the same game (Mike Young on May 28, 1987). He also joined Boog Powell ('66) and Eddie Murray ('80) as the only three Orioles to homer in the 9th inning and in extras in the same game. Mancini finished the season batting .293/.338/.488 with a .826 OPS, 120 OPS+, 24 home runs and 78 RBI in 147 games during his rookie campaign. He also collected 159 hits on his way to finishing in third place for American League Rookie of the Year voting.
Mancini batted leadoff for 51 of 156 games played in 2018. He ended the season hitting .242 with 24 home runs and 58 RBIs. Mancini was leading the Orioles in most offensive categories in late-April. He is one of three MLB players along with Alex Bregman and Anthony Rendon with at least 35 doubles, 34 home runs and 100 runs in 2019. He set a career high with five hits in an 11–4 win over the Toronto Blue Jays at Rogers Centre on September 24, 2019. He ended the season hitting .291 with 35 home runs and 97 RBIs. Mancini was awarded the 2019 Louis M. Hatter Most Valuable Oriole Award by members of the local media.
On March 7, 2020, Mancini left the Orioles during spring training to undergo a non-baseball medical procedure. On March 12, it was revealed that the procedure was the removal of a malignant tumor from his colon. On April 28, Mancini revealed he had stage 3 colon cancer and began chemotherapy to treat his cancer. On June 28, Mancini was placed on the 60-day injured list and missed the entire 2020 season due to recovery from Stage 3 colon cancer surgery. He completed chemotherapy in November 2020.
In November 2020, Mancini announced that he was cancer-free and planned to play for the Orioles in 2021. He returned to the Orioles at the beginning of spring training and appeared in the team's first game of the preseason, against the Pittsburgh Pirates. Mancini was given a standing ovation by the Orioles crowd prior to his first at-bat of the season in Baltimore. He finished the 2021 season batting .255/.326/.432 with 21 home runs and 71 RBIs in 147 games. On November 22, 2021, Mancini was awarded the American League Comeback Player of the Year Award.
On July 28, 2022, Mancini hit an inside-the-park home run with a runner on base that started as what appeared to be a routine sacrifice fly. However, the ball deflected off the cheek of Tampa Bay Rays right fielder Josh Lowe after he lost it in the afternoon sun, allowing Mancini to score. It was a very memorable at-bat for Orioles fans for two reasons: 1. Due to the park’s commemoration of Mo Gaba, Baltimore’s number one sports fan who passed on the same day in 2020, and 2. It ended up being Mancini's final at bat as an Oriole at Camden Yards.
