Waddell was remarkable as a strikeout pitcher in an era when batters mostly slapped at the ball to get singles. He had an excellent fastball, a sharp-breaking curve, a screwball and superb control (his strikeout-to-walk ratio was almost 3-to-1, and he led the American League in strikeouts six years straight). However, he was odd and unpredictable: he had a habit of leaving the dugout in the middle of games to follow passing fire trucks to fires, and performed as an alligator wrestler in the offseason. He was an alcoholic for much of his adult life (Sporting News called him "the sousepaw"), and his eccentric behavior led to constant battles with his managers and scuffles with bad tempered teammates. Recent commentators (such as Bill James) have suggested that Waddell may have suffered from a developmental disability, mental retardation, or autism.

In his career, Waddell had a record of 193-143, 2316 strikeouts, and a 2.16 earned run average, with 50 shutouts and 261 complete games in 2961 innings pitched.

Rube Waddell died in San Antonio, Texas at 37 years of age, apparently from illness contracted while doing flood relief work. He was elected to the Baseball Hall of Fame in 1946.