He played in Major League Baseball from 1907 to 1918 for the Philadelphia Phillies, Cincinnati Reds, Pittsburgh Pirates and Cleveland Indians.

In 1907 he set one of the longest-lived records in major league history when he pitched 25 innings before giving up the first earned run of his career.

Although others have pitched more consecutive innings without an earned run, until July 2008 no one had gone longer without prior major league experience.

McQuillan's extraordinary success as a rookie was no fluke: he posted a 1.69 ERA in his first four seasons, comprising more than 800 innings pitched; during those years his Adjusted ERA+ (the ratio of the league's ERA, adjusted to the pitcher's ballpark, to that of the pitcher) was a staggering 164.

McQuillan's major league career was cut short due to his chronic alcoholism and infection by syphilis.