NOTE: Due to a strike in mid-season, the season was divided into a first half and a second half. The division winner of the first half (denoted East 1, West 1) played the division winner of the second half (denoted East 2, West 2).
March 11 – Johnny Mize and Rube Foster are elected to the Hall of Fame by the Special Veterans Committee. Mize hit .312 with 359 home runs in 15 seasons for the Cardinals and New York Giants, while Foster was a star pitcher, manager and pioneer of the Negro Leagues during the first quarter of the 20th century.
April 9 – After pitcher Jerry Reuss pulls a muscle, rookie Fernando Valenzuela is given his first starting assignment. His first Major League start results in a five-hit shutout. It is the beginning of what will be called "Fernandomania" in Southern California.
April 18 – 19 – Minor league teams from Pawtucket and Rochester clash in a 33 inning game that extends eight hours and 25 minutes; the longest professional baseball game up to that time. Future Hall of FamersWade Boggs and Cal Ripken, Jr. go a combined 6-for-25 in the game.
April 27 – Just 18 days after his first start, Fernando Valenzuela has grabbed the attention of the baseball world. In just his fifth start, he pitches his fourth complete game shutout running his record to 5–0 with a microscopic 0.20 ERA. He is also batting over 0.400 to help his own cause.
April 29 – Steve Carlton of the Philadelphia Phillies records his 3000th career strikeout. April 1981 is the only month in history to have two pitchers reach this milestone. He is the first left-handed pitcher in Major League history to reach that mark.
June 12 – After meeting with major league owners for most of the previous day, players' union chief Marvin Miller announces, "We have accomplished nothing. The strike is on", thus beginning the longest labor action to date in baseball history. By the time the season resumes on August 10, 706 games (38 percent of the season schedule) will have been canceled.
August 6 – As a result of the nearly two-month interruption in play because of the strike, major league owners elect to split the 1981 season into two halves, with the first-place teams from each half in each division (or a division's runner-up team in the second half, if the same club were to win both halves[The Sporting News Official Baseball Guide for 1982, p. 13]) meeting in a best-of-five divisional playoff series. The last time the major leagues had played a split season was 1892. The Oakland Athletics, New York Yankees, Philadelphia Phillies and Los Angeles Dodgers suddenly find themselves guaranteed playoff spots as first-half champions (a problem noted at this time is that those teams will not have much left to play for in that year's regular season).
September 4 – In the conclusion of the longest game in Fenway Park history, the Seattle Mariners beat the Boston Red Sox 8–7 in 20 innings. The game began on September 3, but was suspended after 19 innings with the score tied 7–7.
September 6 – Despite having won the first-half American League East title, New York Yankees manager Gene Michael is replaced by Bob Lemon, who managed the club in 1978–79. The Yankees are under .500 in the second half of the season.
October 3 – Bob Horner hits two home runs and scores the winning run to give the Atlanta Braves a 4–3 win over the Cincinnati Reds, and the Houston Astros the second-half title in the NL West division. Cincinnati, which lost the first-half title to the Dodgers by half a game, will finish with the best overall record (66–42) in the major leagues, but will miss the playoffs as a result of not having won either half's division title.
October 3 – The Milwaukee Brewers (playing since 1970) and Montreal Expos (since 1969) clinch their first postseason appearances. Milwaukee beats Detroit 2–1 to wrap up the second-half title in the AL East division, while Montréal edges the Mets 5–4 to win the NL East's second playoff spot. (St. Louis finishes with the best overall record in the NL East but misses the playoffs for the same reason as the Cincinnati Reds.)
October 5 – The Kansas City Royals shut out Cleveland 9–0 in the first game of a scheduled doubleheader to clinch the second-half title in the AL West. The second game is canceled as irrelevant. This was a make-up game after the scheduled season ended the day before.
December 2 – Following the strike-shortened season, Los Angeles Dodgers pitcher Fernando Valenzuela becomes the third consecutive Dodgers player to be named National League Rookie of the Year. The Mexican lefthander posted a 13–7 record with a 2.48 ERA and led the NL in strikeouts (180), games started (25), complete games (11), shutouts (eight) and innings pitched (1921⁄3). His 13 wins tied him with Steve Carlton in second place behind Tom Seaver, who finished with 14. Valenzuela also made his first All-Star appearance and received both the Cy Young and TSN Rookie of the Year awards.
January 26 – Ray Oyler, 42, shortstop known for excellent glovework with the Detroit Tigers' 1968 champions, afterwards taken in the expansion draft by the Seattle Pilots
February 2 – Al Van Camp, 77, first baseman/left fielder who played from 1928 to 1932 for the Cleveland Indians and Boston Red Sox
February 4 – Grant Gillis, 70, utility infielder for the Washington Senators and Boston Red Sox between 1927 and 1929
February 15 – Cotton Pippen, 69, pitcher for the St. Louis Cardinals, Philadelphia Athletics and Detroit Tigers from 1936 to 1940, better known as the pitcher that struck out Ted Williams in his first major league at-bat
March 7 – Pee-Wee Wanninger, 78, backup shortstop for the Yankees, Red Sox and Reds, better known as the player who replaced Everett Scott with the Yankees in 1925 to end his then major league record of 1,307 consecutive games
March 10 – Bob Elson, 76, broadcaster for the Chicago White Sox from 1931 to 1970; also worked with the Cubs and Oakland Athletics
March 17 – Paul Dean, 67, pitcher who joined his older brother Dizzy on the St. Louis Cardinals, winning 19 games in each of his first two seasons; the brothers each won two games in the 1934 World Series
March 19 – Frank Lane, 85, general manager of the White Sox, Indians, Brewers and Cardinals known for his numerous trades
March 25 – Red Morgan, 97, third baseman for the 1906 Boston Americans, at the time of his death the oldest living former major leaguer
April 16 – Effa Manley, 84, owner of the Negro Leagues' Newark Eagles from 1935 to 1948
April 27 – Emerson Dickman, 66, pitcher for the Boston Red Sox between 1936 and 1941, who later became a coach at Princeton University in the 1950s
May 26 – George Smith, 79, pitcher who played from 1926 to 1930 for the Detroit Tigers and Boston Red Sox
July 1 – Dan Daniel, 91, sportswriter for The Sporting News and various New York newspapers for over 50 years; also a member of baseball's Rules Committee
July 8 – Merl Combs, 61, shortstop for the Boston Red Sox, Washington Senators and Cleveland Indians between 1947 and 1952
August 9 – Sammy T. Hughes, 70, 6-time All-Star second baseman of the Negro Leagues, mainly with the Elite Giants
October 4 – Freddie Lindstrom, 75, Hall of Fame third baseman for the New York Giants who batted .311 lifetime, twice collecting 230 hits and batting .333 in the 1924 World Series at age 18; later coach at Northwestern
October 17 – Johnny Peacock, 71, catcher for the Boston Red Sox, Philadelphia Blue Jays/Phillies and Brooklyn Dodgers, between 1937 and 1945
October 22 – Taffy Wright, 70, outfielder for the Washington Senators, Chicago White Sox and Philadelphia Athletics from 1938 to 1949
October 25 – Pete Reiser, 62, All-Star center fielder for the Brooklyn Dodgers who led the NL in batting and four other categories in 1941 and in steals twice, but whose fearless defensive style led to numerous injuries
December 10 – John F. Kieran, 89, New York sportswriter and radio and television personality who authored books on numerous subjects
December 22 – Ed Gallagher, 71, pitcher for the 1932 Boston Red Sox
December 28 – John Bischoff, 87, catcher for the Chicago White Sox and Boston Red Sox in the 1920s, and one of the first foreign ballplayers to play in Cuban baseball