Mancini made the Orioles' 2017 Opening Day roster after transitioning to the outfield. He pinch-hit in the tenth inning on Opening Day and collected his first hit of the season. On April 12, in a game against the Red Sox in Boston, Mancini went 2-for-3 with a walk, two home runs and four RBIs. On April 16, 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 players first 12 career games with seven. On April 22, in a 4-2 victory over the Red Sox, 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 Pirates, Mancini hit a game-tying, pinch-hit two-run home run in the ninth inning off Pirates closer Tony Watson. Two innings later, with two on and two outs, Mancini hit a walk-off three-run home run off of 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 just 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. On June 25, Mancini hit a home run off of Jake Odorizzi in the 6th inning of a game against the Tampa Bay Rays. The home run was Mancini's fourteenth of the year, giving him the most home runs before an All-Star break by an Orioles rookie.

This Baltimore Orioles Rawlings authentic full size batting helmet was signed in black by Mancini and includes a JSA sticker and COA.