Three weeks after graduating, Coombs pitched in his first major league game for Philadelphia, which was a 7 hit shutout, defeating the Washington Senators 3-0. He finished 1906 with a 10-10 record and 2.50 ERA. In 1906, he pitched the longest complete game in the American League, 24 innings against Boston, winning 4-1.  The following year was not great as Coombs went 6-9 with a 3.12 ERA. In 1908 and 1909 his record was only 19-16 despite his ERA being 2.00 and 2.32 those years.
His best season was 1910 which is still one of the best single pitching seasons in MLB history. Besides his record of 31–9, he led the American League in wins (31), games played (45), and shutouts (13), which is still the single season AL record. He won 18 of 19 starts that July and racked up 53 consecutive scoreless innings which was the major league record until Walter Johnson broke it three years later. Don Drysdale and Orel Hershiser have since broken the mark.