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 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 .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.
May 21 – Ron Darling of Yale University pitches a no-hitter through eleven innings against St. John's University. In the 12th inning, St. John's broke up the no-hitter and then scored on a double-steal to beat Yale 1-0. Darling's performance remains the longest no-hitter in NCAA history and the game is considered by some to be the best in college baseball history. Frank Viola was the opposing pitcher for St. John's.
June 10 – Pete Rose hits a Nolan Ryan pitch in his first at-bat for the 3,630th safe hit of his career; tying Stan Musial's National League record for career hits. He would strike out in his next three at-bats in the game, however, in his bid to break the record.
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 wild card team if the same club wins both halves) meeting in a best-of-five divisional playoff series. The last time the major leagues 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 the rest of that year's regular season).
August 24 – Kent Hrbek debuts as a Minnesota Twin. His twelfth-inning home run beats the Yankees 3-2 in New York. Hrbek will go on to have a 14-year career with his hometown team.
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 give the Houston Astros the second-half title in the NL West division. Cincinnati, which lost the first-half title to the Dodgers by one-half game, will finish with the best overall record (66-42) in the major leagues, but will miss the playoffs due to not winning 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 division'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 division. The second game is canceled as irrelevant. This was a make-up game after the scheduled season ended the day before.
October 28 – Pedro Guerrero drives in five runs, and pitcher Burt Hooton and the Los Angeles Dodgers beat the New York Yankees, 9–2, to win the 1981 World Series in six games. In a remarkable postseason, the Dodgers rallied from a 2-0 deficit against the Astros in the division series, they rallied from a 2 games to 1 deficit against the Expos in the National League Championship series, and they rallied from a 2-0 deficit against the Yankees in the World Series. Guerrero, Ron Cey and Steve Yeager are named co-MVPs.
December 2 – Los Angeles Dodgers pitcher Fernando Valenzuela became the third consecutive Dodgers player to be named National League Rookie of the Year. The Mexican left-hander 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 Award and TSN Rookie of the Year.
January 3 – Lou Fette, 73, All-Star pitcher who posted a 41-40 record and a 3.15 ERA in 109 games with the Boston Braves and Brooklyn Dodgers, leading the National League for the most shutouts in 1937 and 1939.
January 6 – Fred Stiely, 79, pitcher who played from 1929 through 1931 for the St. Louis Browns of the American League.
January 7 – Irv Stein, 69, pitcher for the 1932 Philadelphia Athletics of the American League.
January 17 – Owen Kahn, 75, pinch-hitter in one game for the 1930 Boston Braves.
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.
January 27 – Huck Geary, 64, shortstop for the Pittsburgh Pirates from 1942 to 1943.
January 30 – Marino Pieretti, 60, Italian pitcher who posted 30-38 record and a 4.53 ERA for the Washington Senators, Chicago White Sox and Cleveland Indians from 1945 to 1950.
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 6 – Cactus Keck, 82, pitcher for the Cincinnati Reds from 1922 to 1923.
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.
February 19 – Sam Barnes, 81, second baseman for the Detroit Tigers in the 1921 season.
February 22 – Andy High, 83, National League third baseman who hit a .284 average in 1314 games for five different teams, and a member of the St. Louis Cardinals 1931 World Series Champions.
February 23 – Myrl Brown, 86, pitcher who posted a 3-1 record in seven games for the 1922 Pittsburgh Pirates.
February 25 – Frank McCrea, 84, backup catcher for the 1925 Cleveland Indians.
March 6 – Wade Lefler, 84, backup outfielder who played for the Boston Braves and Washington Senators during the 1924 season.
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 8 – Gowell Claset, 73, pitcher for the 1933 Philadelphia Athletics of the American League.
March 10 – Bob Elson, 76, broadcaster for the Chicago White Sox from 1931 to 1970, who also worked with the Chicago Cubs and Oakland Athletics.
March 11 – Vince Gonzales, 55, Cuban-born Mexican pitcher who played with the Washington Senators in 1955.
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 17 – Joe Giebel, 89, backup catcher in three games for the 1913 Philadelphia Athletics.
March 19 – Zinn Beck, 95, backup infielder who played for the St. Louis Cardinals and New York Yankees, hitting .226 in 124 games between 1913 and 1918.
March 19 – Frank Lane, 85, general manager of the White Sox, Indians, Brewers and Cardinals known for his numerous trades.
March 20 – Gee Walker, 73, All-Star outfielder who played from 1931 through 1945 for the Tigers, White Sox, Senators, Indians and Reds, collecting a career batting average of .294, 1,991 hits, 223 stolen bases, and 124 home runs.
March 25 – Red Morgan, 97, third baseman for the 1906 Boston Americans, at the time of his death the oldest living former major leaguer.
September 13 – León Kellman, 54, legendary Panamanian catcher/manager who led his teams to three championships, was a four-time Negro League All-Star, and became the first player in Mexican baseball history to hit two grand slams in the same game.
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 between the 1938 and 1949 seasons.
October 25 – Pete Reiser, 62, All-Star center fielder for the Brooklyn Dodgers who led the National League in batting and four other categories in 1941 and in steals twice, but whose fearless defensive style led to numerous injuries.