The Kansas City Royals selected Manaea with the 34th pick in the 2013 MLB draft, and traded him to the Athletics during the 2015 season.

Playing for the baseball team at Andrean, Manaea was part of the state champions in 2010, his senior year.

After his freshman year at ISU, Manaea played collegiate summer baseball for the Dubois County Bombers of the Prospect League.

[9][10] Following his sophomore year at Indiana State, he competed for the Hyannis Harbor Hawks in the Cape Cod Baseball League, where he went 5–1 with a 1.22 earned run average (ERA) and a league-leading 85 strikeouts (setting the modern record for a single summer) in 51+2⁄3 innings pitched, and won the league's Outstanding Prospect Award, and was named the B.F.C Whitehouse Top Pitcher, Summer National Player of the Year by Perfect Game USA, and the Cape Cod League's top prospect by Baseball America.

[10][1][5][11][12][13] In 2013, Manaea was named a Preseason All-American[14] and added to the National Pitcher of the Year Watch List.

[6] Considered a top prospect in the 2013 Major League Baseball draft,[1][5] Manaea was scouted by the Houston Astros, who had the first overall pick.

[9][20] Healthy in time for spring training in 2014, the Royals assigned Manaea to the Wilmington Blue Rocks of the High-A Carolina League, with the plan to limit him to 150 innings pitched for the 2014 season.

After making four starts for Wilmington, Manaea received a promotion to the Northwest Arkansas Naturals of the Double-A Texas League in July, for whom he pitched seven innings.

[24] The Royals traded Manaea and Aaron Brooks to the Oakland Athletics on July 28, 2015, in exchange for Ben Zobrist.

[28] After he made three starts for Nashville, with whom he was 2–0 with a 1.50 ERA in 18 innings with 21 strikeouts, the Athletics promoted Manaea to the major leagues to make his debut on April 29.

[35] He struggled with weight loss during the season due to changing dosage of an attention deficit hyperactivity disorder medication he was prescribed in the spring, going from 255 to 230 pounds (116 to 104 kg).

[36][33] On April 21, 2018, Manaea no-hit the Boston Red Sox 3–0 at Oakland-Alameda County Coliseum, becoming the first Athletics pitcher to throw a no-hitter since Dallas Braden's perfect game in 2010.

[33] As Oakland advanced in the playoffs, Manaea pitched against the Houston Astros in Game 2 of the 2020 American League Division Series.

[50] On April 3, 2022, the Athletics traded Manaea and Aaron Holiday to the San Diego Padres for Adrián Martínez and Euribiel Angeles.

[55] On January 12, 2024, Manaea signed a two-year, $28 million contract with the New York Mets including an opt-out after the 2024 season.

[56] On June 26, 2024, Manaea recorded the 1,000th strikeout of his career, fanning Juan Soto in the third inning of a 12–2 victory over the New York Yankees.

[57] Manaea made 32 starts for the Mets in 2024, posting a 12–6 record and a 3.47 ERA with 184 strikeouts across 1812⁄3 innings pitched, setting a new career-high.

[58] Manaea earned the first postseason win of his career on October 8, pitching seven innings of one-run ball against the Philadelphia Phillies in Game 3 of the National League Division Series at Citi Field.