In 1902 Glade appeared in one game for the Chicago National League team. He jumped to the American League in 1904 and gave four years of good services for the awful St. Louis Browns. In his rookie season he went 18–15 with a 2.27 ERA. In addition, on June 19 he set a major league game-record, since then broken, with 15 strikeouts in a 1–0 victory over the New York Highlanders. But Glade led the league with 25 losses in 1905, winning only six games with a solid 2.81 ERA. He rebounded with two winning seasons in 1906 (15-14, 2.36) and 1907 (13-9, 2.67). He was traded to the Highlanders before 1908, his last major league season.
On August 3, 1906 at Sportsman's Park, Glade faced Long Tom Hughes and the Washington Senators, entering the 10th inning with a scoreless tie, until Hughes decided the game with a solo home run to a 1–0 victory, becoming the first pitcher in major league history to pitch a shutout and hit a home run which accounted for the only run in the game.