The Orioles promoted Means to the major leagues on September 24, 2018.[11] After a competition in spring training, the Orioles named Means to the team's Opening Day roster as a relief pitcher for the 2019 season.[12] After three appearances out of the bullpen, pitching to a 1.59 ERA in 52⁄3 innings, Means was moved into the Orioles' starting rotation.[13]
On June 28, 2019, Means was selected to his first All-Star Game, his 2.50 ERA ranking second among American League pitchers for the first half of the season.[1] Starting 27 of 31 pitching appearances, he completed his rookie campaign at 12–11 with a 3.60 ERA.[14] He finished second in American League Rookie of the Year voting.[15] In the 2020 season, which was shortened by the COVID-19 pandemic, Means pitched to a 4.53 ERA, 42 strikeouts and a 2–4 record over 43+2⁄3 innings pitched in 10 games pitched, all starts.[16]
The Orioles selected Means as their Opening Day starting pitcher for the 2021 season.[17] On May 5, 2021, he threw a no-hitter against the Seattle Mariners, striking out 12 batters while facing the minimum of 27 batters. His only baserunner, Sam Haggerty, reached on a dropped third strike in the third inning and was subsequently caught trying to steal second base. It was the first no-hitter for the Orioles since 1991 and the first solo no-hitter since Jim Palmer no-hit the Oakland Athletics on August 13, 1969.[18] It was also the first no-hitter in MLB history where the only baserunner reached base on an uncaught third strike.[19] On May 10, Means was named the AL Player of the Week for week of May 3 to May 9.[20][21] On June 6, Means went onto the 10-day injured list with a strained shoulder.[22] Means was activated on July 20, after missing over a month of action.[23]
Means was named the Opening Day starter for the 2022 season,[24][25][26] and pitched on April 7 against the Tampa Bay Rays. On April 13, Means pitched four innings against the Milwaukee Brewers before his removal from the game.[27] He was diagnosed with elbow strain two days later and placed on the 10-day injured list.[28][29][30] Means was transferred to the 60-day IL on April 17.[31][32] Doctors determined that Means needed Tommy John surgery, which prematurely ended his 2022 season.[33][34] He underwent surgery on May 11, 2022. On May 21, Means agreed to a two-year, $5.925 million contract with the Orioles to avoid arbitration.[35]
Means spent the majority of the 2023 season rehabilitating from surgery. The Orioles activated him from the injured list on September 12, 2023, and he pitched the first five innings in a 5–2 home loss to the St. Louis Cardinals later that same night.[36][37] Means earned his first win in two years two starts later in a 2–1 away victory over the Cleveland Guardians on September 23 in which he pitched 8+1⁄3 innings including the first 7+2⁄3 without allowing a hit.[38]
After missing brief time in 2024 due to injury, Means returned to make 4 starts and compile a 2.61 ERA with 16 strikeouts across 20+2⁄3 innings pitched. On May 31, 2024, it was announced that Means would be undergoing season-ending surgery to repair damage to his ulnar collateral ligament.[39] On June 3, Means underwent Tommy John surgery for the second time, effectively ending his season.[40]