In his rookie season in the Majors, with the reigning world champion 1943 Cardinals, Klein was a strong contributor to the Redbirds' successful defense of the National League pennant. He appeared in 154 of the club's 157 official games, started 32 games at shortstop, and then succeeded Jimmy Brown as St. Louis' regular second baseman (119 starts) when Brown entered World War II military service. Klein hit a career-high .287 and was second on the Cardinals in hits (180), runs scored (91) and triples (14)—behind only Stan Musial, an eventual Baseball Hall of Famer. During the 1943 World Series against the New York Yankees, he started all five games at second base but he collected only three hits, all singles, in 22 at bats and the Cardinals fell to the Yankees, four games to one. Klein then joined the United States Coast Guard, serving in Maryland and Florida, and missed all of and most of the season.