April 20 – The Boston Red Sox show off their prize rookie Ted Williams before 30,278 in Opening Day at Yankee Stadium, delayed two days because of rain. After striking out twice, Williams collects a double off pitcher Red Ruffing, who wins 2–0. Yankees first baseman Lou Gehrig makes an error, goes hitless, and lines into two double plays in the only game featuring the two great sluggers. Other notables in what will become a historic box score include Joe DiMaggio, Bill Dickey, Jimmie Foxx, Joe Cronin, Bobby Doerr, Red Rolfe, and losing pitcher Lefty Grove. The Yankees score their first run on a home run by Dickey and their second tally on an error by Foxx. Boston has baserunners in each inning, but Ruffing tosses just the second opening day shutout in Yankees history. Four umpires work the game including third base umpire George Pipgras, the starting pitcher for the Yankees in the 1929 opener; his opponent for the Red Sox that day was Ruffing.
April 29 – In the seventh game of the season, New York Yankees center fielder Joe DiMaggio makes a sharp turn while fielding a liner facing the Washington Senators and tears muscles in his right foot. The Yankees lose the game and DiMaggio will miss the next 35 games.
April 30 – Lou Gehrig goes hitless in four at-bats against the Washington Senators and is now hitting just .143 this season. He had just played his 2,130th consecutive major league game. No one knew it would be the very last of his career.
July 4 – Lou Gehrig day was held at Yankee Stadium. Numerous people, including many from other major league teams, came forward to give Gehrig gifts and to shower praise on the dying slugger. The Yankees retired his uniform number 4; the first player in major league history to be afforded that honor. Babe Ruth even showed up and ended their long-standing feud by giving his old teammate a hug. After the presentations, Gehrig approached the microphone, and addressed the crowd: "Fans, for the past two weeks you have been reading about a bad break I got. Yet today, I consider myself the luckiest man on the face of the earth. I have been to ballparks for seventeen years and I have never received anything but kindness and encouragement from you fans."
December 6 – In a trade of veteran shortstops, or "worn-out shortstops", as one newspaper described it, the Chicago Cubs acquire Billy Rogell from the Detroit Tigers for Dick Bartell. Rogell, who injured his arm playing handball the previous year, hits just .136 before hanging up his spikes. The Tigers will release "Rowdy Richard" five games into the 1941 season, but he will stick with the New York Giants until 1946.