Ramírez's first major league game was as a pinch runner for the Indians in the ninth inning, where he scored on a game-winning grand slam hit by Mike Avilés. A week later, Ramírez recorded his first major league hit, which was a single to left field off of Royals starter Ervin Santana. This hit was essential for Ramírez as it was his first of many. Throughout the season, he hit .262 in 237 at-bats, compiled 62 hits, and had 10 steals.

In 2016, Ramírez hit .312/.355/.423 and became the first player during that year to hit in every spot in the lineup when he batted fourth on June 28. Ramírez had also played four positions that year: second base, third base, shortstop, and left field. When asked about Ramírez's play, Indians hitting coach Ty Van Burkleo noted that Ramírez "has done a great job all year."

In the 2017 season, Ramírez hit his 17th home run of the season in a 9–1 victory versus the Chicago White Sox, becoming only the second hitter in Cleveland Indians to have hit that many home runs before the end of May. Ramírez also achieved 30 home runs and 30 stolen bases, becoming the first Indian to do so since 2012. He ended the season with 56 doubles, a .318 batting average, 29 home runs, 83 RBI, and 107 runs scored.

The 2018 season started off slowly for Ramírez as he dealt with a thumb injury. Still, he finished the season with 23 home runs, 83 RBI, and 24 stolen bases. In the 2020 season, Ramírez batted .292 with a .386 OBP and career-highs in OPS (.993), slugging percentage (.607), and OPS+ (163). He also tallied 64 hits, 45 runs scored, 16 doubles, 17 home runs, 46 RBI, 133 total bases, 34 extra base hits, 31 walks, and ten stolen bases.

Throughout his career, José Ramírez has had some of the best plays in the MLB. From his first hit to his game-winning home runs and stolen bases, Ramírez has been essential to the Cleveland Guardians. Ramírez's ability to hit in different spots in the lineup and play different positions has made him a valuable player to the team. The future looks bright for Ramírez, and fans are excited to see what plays he will bring to the game.