The 2013 Major League Baseball season started on March 31 with a Sunday night game between the Texas Rangers and the Houston Astros. Opening Day for most clubs was a day later on April 1. The regular season ended on September 30, extended one day for a one-game playoff between the Tampa Bay Rays and the Texas Rangers to decide the second American League Wild Card winner.

The 2013 season was the first with the Houston Astros as a member of the American League (AL), playing in the West Division. This marked the first growth in the number of American League teams since the 1977 Major League Baseball expansion added the Seattle Mariners and Toronto Blue Jays. When the then-named Tampa Bay Devil Rays were added to the AL in 1998, the Milwaukee Brewers were reassigned to the National League (NL) the same year, keeping the AL at 14 teams. With the Astros' move to the AL, giving both leagues 15 teams, interleague play occurred throughout the entire season for the first time in MLB history.

The Major League Baseball All-Star Game's 84th edition was held on July 16 at Citi Field, home of the New York Mets, with the AL defeating the NL, 3–0. With the win, home field advantage at the World Series was awarded to the AL.

The season ended with the Boston Red Sox winning the World Series at Fenway Park for the first time since 1918, defeating the St. Louis Cardinals in six games. The Red Sox's victory recovered the city of Boston six months after the marathon bombing. This marked the last time a team clinched the World Series on their home field until 2022, where the Houston Astros won their second championship at Minute Maid Park.

Several minor rule changes took effect during the 2013 season. These changes were approved by MLB owners; unless otherwise noted, they will also need the approval of the players' union.

At the end of the 2012 season, the following teams made replacements to their managers.

The Houston Astros' move to the American League West created two 15-team leagues each separated into three five-team divisions. With an odd number of teams in each league, interleague games were played nearly every day during the season, the only exception being when not every team had a game. For this season, each team played 20 interleague games (up from 15–18 games in 2012) in eight series. Each team played one three-game series against four teams from one division in the other league, and two two-game series (one home, one away) against the remaining team in that division (for 2013 the match-ups are AL East vs. NL West, AL Central vs. NL East, and AL West vs. NL Central, meaning the changes of the Astros and the small increase in interleague play will not affect the yearly rotation, also the Astros played all their former NL Central rivals in 2013). The remaining four games were played against a team's "natural rival" in two back-to-back two-game series from May 27–30. Teams played in one city May 27 and 28, then traveled to the other city for games on May 29 and 30. It was the first season that every team has an interleague rivalry, according to the table below, with new rivalries for the season shown in italics.

The remaining 142 games will be played within the league. Each team will play its four division rivals 19 times (up from 15–18 in 2012) for a total of 76 games. Each team will play either 6 or 7 games against the ten teams in the two other divisions in its league, for a total of 66 games. In 2012, these season series ranged anywhere from five to ten games, creating large disparities between teams' strengths of schedule.