Lazzeri debuted in the major leagues in 1926 as a member of the Yankees. Manager Miller Huggins moved Lazzeri from shortstop to second base. Huggins paired Lazzeri with Mark Koenig, also a rookie, as his double play combination. In his rookie season, playing all 155 games, Lazzeri hit 18 home runs and had 114 RBIs. He finished third in the American League (AL) in home runs behind Babe Ruth and Al Simmons, and tied for third in RBIs with George Burns, trailing only Ruth. The Yankees reached the 1926 World Series, losing to the St. Louis Cardinals. In a bases loaded situation in the seventh inning of the deciding game, Grover Cleveland Alexander struck out Lazzeri to save the series for the Cardinals.