In 2017, as a freshman at West Virginia, Manoah appeared in 19 games (ten starts), pitching to a 1–1 record with a 3.07 ERA,[5] earning a spot on the Big 12 All-Freshman Team.

[25] On May 27, 2021, Manoah was selected to the 40-man roster and promoted to the major leagues for the first time, and started against the New York Yankees that day, while picking up the win in a 2–0 final.

[29] Manoah finished his rookie season with the Blue Jays having started twenty games in which he went 9–2 with a 3.22 ERA and 127 strikeouts over 111+2⁄3 innings.

[30] Manoah was selected to represent the Blue Jays alongside teammates Santiago Espinal, George Springer, Alejandro Kirk, and Vladimir Guerrero Jr. in the 2022 Major League Baseball All-Star Game.

Manoah also finished third in Cy Young Award voting, behind Dylan Cease of the Chicago White Sox and winner Justin Verlander of the Houston Astros.

[33] Coming off his first two major league seasons, expectations were high for Manoah, who was selected as Toronto's opening day starter.

Manoah, however, reacted negatively to his demotion and did not report to the Bisons, and subsequently informed the Blue Jays that he would not pitch again during the 2023 season.

American baseball journalist Buster Olney later opined, "Every year there are literally dozens of players who get sent down and don't agree with the decision, but they get on the bus, get on the plane, they go down, they report to go to work to prove the team wrong.

"[40] Following the demotion to Buffalo, Manoah met with specialists who examined his knee, back and right quadricep, with no structural damage being found.

[43] In Manoah's absence, the Blue Jays secured a playoff spot, playing the Minnesota Twins in the best-of-three AL Wild Card Series.

[44] At season's end, GM Ross Atkins reiterated that no structural damage had been found, but that Manoah had recently received "an injection" to relieve discomfort in his right shoulder, and that team doctors had no input in that decision.

[49] Manoah features an upper 90s mph fourseam fastball, a mid 90s sinker, a changeup, and a slider that he learned from watching Dellin Betances on Rob Friedman's Twitter account, PitchingNinja.