May 22 – In their first meeting of the season, the Pittsburgh Pirates defeat the New York Giants 8–6 at the Polo Grounds, to improve their record to 25–6 and to increase their lead over the second place Giants to 4.5 games. After trailing for most of the game, the Pirates scored twice in the eighth and six times in the ninth.
July 12 – Babe Ruth hits his 33rd and 34th home run of the season. His 33rd home run gave him 136 career home runs, tying Roger Connor's all-time mark. His 34th home run makes him the all-time home run king, a title he will hold until 1974.
August 9 – The St. Louis Browns defeat the Washington Senators 8–6 in nineteen innings. Dixie Davis pitches all nineteen innings for St. Louis.
August 19 – Ty Cobb of the Detroit Tigers becomes the fourth player with 3000 career hits.
August 27 – With a 3–1 victory at the Polo Grounds, the New York Giants complete a five-game sweep of the visiting Pittsburgh Pirates to move within 2.5 games of first place Pittsburgh. The Giants out scored the Pirates 27–6 in the series.
September 9 – The Detroit Tigers and Chicago White Sox lock up in a slugfest at Comiskey Park. The Tigers collect twenty hits and six walks on their way to scoring fifteen runs. However, the White Sox score twenty runs on 22 hits, including a home run by Earl Sheely.
In the first game of a crucial three game series for first place in the National League, the New York Giants' Fred Toney holds the Pittsburgh Pirates to two hits in the Giants' 5–0 victory.
September 17 – The New York Giants complete a ten-game winning streak that sees them go from a half game back of the Pittsburgh Pirates in the National League to first place, 4.5 games up.
September 20 – With a 4–2 victory over the Detroit Tigers, and a 7–4 loss by the Cleveland Indians at the hands of the Boston Red Sox, the New York Yankees capture first place in the American League, and hold it for the remainder of the season.
September 25 – The New York Yankees defeat the Cleveland Indians 21–7. Surprisingly, none of the 21 runs scored are driven in by Babe Ruth, who goes on to compile one of the greatest single seasons of batting in Major League baseball history by hitting 59 home runs, driving in 171 runs, scoring 177 runs with 204 hits for a .378 batting average in only 540 At-Bats. His On-base percentage for the season is .510 and his slugging percentage is an astounding .846 mark. Ruth's 59 home runs are more than the other seven American League team home run totals combined.
October 2 – The Philadelphia Athletics lose 11–6 to the Washington Senators for their 100th loss of the season, giving both Philadelphia teams 100 losses for the season.
October 5 – The New York Yankees defeat the New York Giants 3–0 in the first World Series game in franchise history. The Series is the first to be broadcast on radio. Announcer Thomas Cowan recreated the game over Westinghouse-owned WJZ in Newark, listening to phoned-in reports from the stadium.
October 6 – The Yankees defeat the Giants in the second game of the World Series by the same score of the first game, 3–0.
October 7 – After having been outscored 10–0 in the World season, and falling behind 4–0 to the Yankees in game three, the Giants explode for thirteen runs, and defeat the Yankees 13–5.
October 9 – The New York Giants even the 1921 World Series at two games apiece with a 4–2 victory. Babe Ruth homers in the bottom of the ninth.
October 10 – Babe Ruth catches the New York Giants' infield off guard as the Yankee slugger bunts his way on to lead off the fourth inning. The strategy works, as Ruth scores the winning run in the Yankees' 3–1 victory.
October 11 – The New York Giants battle back from 3–0 and 5–3 deficits to beat the Yankees 8–5 in game six of the World Series.
October 13 – The New York Giants defeat the New York Yankees, 1–0, in Game eight of the World Series to capture their second World Championship, five games to three. For the first time in World Series play, all games were held at one site: the Polo Grounds in New York, with the home team alternating. The Yankees sub-leased the Polo Grounds from the New York Giants from 1913 through 1922.
October 27 – Bill Kuehne, 63, German third baseman for the Columbus Buckeyes, Pittsburgh Alleghenys & Burghers, Columbus Solons, Louisville Colonels, St. Louis Browns, and Cincinnati Reds during the 19th century.