Meadows suffered a broken orbital bone in his right eye during spring training in 2016.[11] He returned to Altoona and earned a promotion to the Indianapolis Indians of the Triple–AInternational League in June.[13] In 45 games for Altoona he batted .311 with six home runs and 23 RBIs in 45 games, and in 37 games for Indianapolis, he compiled a .214 batting average with six home runs and 34 RBIs. The Pirates invited Meadows to spring training in 2017.[14] Meadows returned to Indianapolis for the 2017 season,[15] where he posted a .250 batting average with four home runs and 36 RBIs in 72 games.[16] He missed nearly two months of the season due to hamstring and oblique strains. The Pirates added him to their 40-man roster after the 2017 season.[17]
Meadows with the Pirates in 2018
MLB.com ranked Meadows as Pittsburgh's second best prospect going into the 2018 season.[18] He began the season with Indianapolis and was promoted to the major leagues to make his debut on May 18.[19] He recorded his first major league hit off of Tyson Ross, as well as his first stolen base, that same night. On May 20, 2018, he hit his first major league home run off of Jordan Lyles.[20] Meadows was named the National League Rookie of the Month for the month of May after batting .409 with four home runs, seven RBIs, three doubles, and three stolen bases in 13 games during the month.[21]
In 2019, Meadows made his first All-star game. He ended the 2019 season with career highs offensively. He led the team in average (.291), home runs (33), runs (83) and 89 runs batted in in 138 games.[23]
On July 16, 2020, Meadows was placed on the injured list after he tested positive for COVID-19, which caused him to miss the beginning of the abbreviated 2020 season. After recovering from the illness, he returned to the Rays on August 4.[24][25] During the season, Meadows hit .205/.296/.371 in 36 games.
In 2021 he had the lowest ground ball/fly ball ratio in the major leagues, at 0.54, and the lowest ground ball percentage, at 28.7%.[26] He finished the 2021 season with a .234 batting average, with 27 home runs and 106 RBIs.
Detroit Tigers
On April 4, 2022, Meadows was traded to the Detroit Tigers in exchange for Isaac Paredes and a competitive balance round B pick in the 2022 MLB draft.[27] After leaving the Tigers early in the season due to vertigo and later COVID-19, Meadows returned to the team in June only to go on the injured list again with tendinitis in his Achilles. He would not return to the Tigers the rest of the season, adding that he was suffering from mental health issues in addition to his physical ailments.[28] In 36 games with the Tigers in 2022, Meadows batted .250 with no home runs.
On November 25, 2022, the Tigers and Meadows agreed on a one-year, $4.3 million contract for the 2023 season, avoiding salary arbitration.[29] On April 8, 2023, Meadows was placed on the injured list with anxiety issues. The Tigers president of baseball operations Scott Harris issued a statement supporting Meadows' decision to step away from the game to seek help.[30] On May 1, Meadows was transferred to the 60-day injured list.[31] On September 9, it was announced that Meadows would not return to the Tigers in 2023.[32] On November 17, 2023, it was announced that the Tigers would not tender Meadows a contract for the 2024 season, making him a free agent.[33]