Returning to Salt Lake City under new manager Oscar Vitt in 1925, Lazzeri batted .355 with 60 home runs and 222 runs batted in (RBIs), the most RBIs in professional baseball history. That year he became one of what are today four Pacific Coast League hitters to have had a 30 home runs, 30 stolen bases season, along with Joc Pederson (2014), Frank Demaree (1934), and Lefty O'Doul (1927). Though Salt Lake City had a working agreement with the Chicago Cubs, the Cubs passed on Lazzeri due to his epilepsy. The Cincinnati Reds passed on Lazzeri as well. Bill Essick, a scout for the New York Yankees, convinced Ed Barrow, the Yankees' general manager, to sign Lazzeri. Barrow agreed after receiving confirmatory reports from other scouts, including Ed Holly and Paul Krichell, as well as ensuring that Lazzeri's insurance policy would cover his illness.
After the 1925 season, Barrow purchased Lazzeri from Salt Lake City in exchange for the rights to Frank Zoeller and Mack Hillis and $50,000 ($728,937 in current dollar terms). Lazzeri signed a contract with the Yankees worth $5,000 ($72,894 in current dollar terms).
Although his offensive production was overshadowed by the historic accomplishments of teammates such as Babe Ruth, Lou Gehrig and Joe DiMaggio, Lazzeri is still considered one of the top hitting second basemen of his era. Koenig considered Lazzeri the team's most valuable player. He finished his career with a .292 batting average, 986 runs, 178 home runs, 1,191 RBI and 148 stolen bases. Despite his hitting 60 home runs in an extended PCL season in 1925, Lazzeri never hit more than 18 home runs in a major league season (a mark he reached four times).