Groom's best major league season was with the 1912 Senators, when he won 24 games and Washington finished second in the American League. During his debut season, Groom became the first pitcher to achieve 19 consecutive losses in a season, a record which was equalled in 1916 by Jack Nabors.
In September 1916, Groom was also involved in a confrontation with George Sisler, the Browns' normally mild-mannered first baseman. After an inning in which Sisler missed a high throw to first base, Groom yelled, "Listen, you...college boy, you run harder for those...balls. Where the hell do you think you are, at a...tea party?" Pale-faced, Sisler stared momentarily at Groom, then strolled over and punched the pitcher in the mouth with his left fist. Groom never yelled at his teammate again.
On May 6, 1917, while with the Browns, Groom no-hit the eventual World Champion Chicago White Sox 3–0. The no-hitter came in the second game of Sunday double-header, after Groom preserved the win in the first game, pitching the last two innings without allowing a hit. It also came the day after teammate Ernie Koob's 1–0 no-hitter against the White Sox; to date, Koob and Groom are the only teammates to pitch no-hitters on consecutive days.

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