He was a pitcher for the New York Giants of the National League from 1928 to 1943, and remained on the team's payroll for the rest of his life, long after their move to San Francisco.

He is perhaps best remembered for his performance in the 1934 All-Star Game, when he struck out five future Hall of Famers – Babe Ruth, Lou Gehrig, Jimmie Foxx, Al Simmons and Joe Cronin – in succession.

In 1925, he went 17–13 with the Oklahoma City Indians of the Western League with his trademark screwball; as a result, he was signed by the Detroit Tigers and was invited to spring training in 1926.

However, pitching coach George McBride and player-manager Ty Cobb wanted him to scrap the screwball due to fears of injuries.

Without his signature pitch, Hubbell went a mediocre 7–7 on a championship team and was demoted to the Decatur Commodores of the Illinois–Indiana–Iowa League after spring training 1927.

[2][3] Hubbell was so fed up by this time that he told Beaumont manager Claude Robinson that he would retire and go into the oil business unless he was sold to another organization by the end of the season.

Kinsella called Giants manager John McGraw and mentioned that he knew of Hubbell's release by Detroit, prompted in part by Cobb's concerns about the screwball.

With a slow delivery of his screwball, Hubbell recorded five consecutive 20-win seasons for the Giants (1933–37) and helped his team to three NL pennants and the 1933 World Series title.

Time said that while he was growing up on his family's Missouri farm, he "practiced for hours...throwing stones at a barn door until he could unfailingly hit knotholes no bigger than a dime".

[4] However, Giants owner Horace Stoneham immediately appointed him as director of player development, a post he held for 35 years.

In the 1934 All Star Game played at the Polo Grounds, Hubbell produced one of baseball's most memorable moments by striking out five future Hall of Famers in succession: Babe Ruth, Lou Gehrig, Jimmie Foxx, Al Simmons and Joe Cronin.

[7] In 1984, the 50th anniversary of this legendary performance, Hubbell was on hand for the 1984 All-Star Game at San Francisco's Candlestick Park to throw out the first pitch, which was a screwball.

Hubbell suffered a stroke while driving near his home in Mesa, Arizona, on November 19, 1988, that caused him to lose control of his car and crash into a lamppost.