Interleague play was an innovation in Major League Baseball during the 1997 season. Prior to 1997, teams from the American League and National League would play each other only in spring training and during the World Series, while their players would face one another in the All-Star Game. During this time, the leagues had gained a unique identity and players prided themselves on being a member of their league.
Originally, interleague games were limited to a few windows during the season, during which every team played an opponent from the other league (except in the National League, which had 16 teams to the AL's 14 from 1998 to 2012, where there had by default to be one intra-league contest to balance things out). Starting in 2013, when the Houston Astros moved to the AL to create two fifteen-team leagues, interleague games needed to be played throughout the season, as it was the only way to have all 30 major league teams active on the same day. Teams played only a selection of the teams from the other league, usually concentrating their interleague games on teams from one division in the opposite circuit, which would change from year to year, plus a few legacy games (such as New York vs. New York). In 2020, due to the need to reduce travel during the Coronavirus pandemic, teams only played against their most direct geographic opponents, but as a whole, the percentage of interlegue games was higher than usual. As part of the Collective Bargaining Agreement adopted after the 2021-2022 lockout, a provision was adopted to play a more balanced schedule of interleague games starting in 2023: by playing five fewer games against their divisional opponents starting that season, teams will be able to play at least one series against every other major league team, raising the number in interleague games from 16 to 46: 3 against 14 teams, and 4 against one team designated as a "direct geographic opponent".
Until 2019, the designated hitter was used in interleague games played in AL ballpark. After using a universal DH during the exceptional 2020 season, AL pitchers once again had to bat when playing in NL parks in 2021. This ended in 2022 when the universal DH was adopted permanently.
It should be noted that interleague games were a common feature of the Negro Leagues, although these did not count in the final league standings. There was a long-standing tradition of teams playing both league contests and games against outside opponents throughout the season, who could include both independent teams and teams from the rival circuit, all of which being taken equally seriously even if the statistical record only includes league games.
The idea for the leagues to play each other, began in 1933 when Bill Veeck Sr. suggested that teams play the other league for six weeks in the summer. The plan received some support but Veeck died later that year and his plan was shelved.
With the Washington Senators moving to Minnesota, there was talk of putting a National League team in New York, creating two nine-team leagues. With the imbalance, there would be one interleague series each day of the season. This plan was shelved when the American League expanded by two teams in 1961 and the National League followed in 1962.
When the American League adopted the designated hitter in 1973, they also voted for interleague play but the plan was rejected by the National League. Commissioner Bowie Kuhn formed a committee to study the matter.
- First Game: San Francisco Giants at Texas Rangers, June 12, 1997
- First Pitch: Darren Oliver
- First Batter: Darryl Hamilton
- First Hit: Hamilton, led off the game with a single
- First Run: Damon Buford
- First Home Run: Stan Javier
- First Home Run by an American League Pitcher: Bobby Witt vs. Dodgers, June 30, 1997
Through the 2010 season, the American League held a 1,808-1,652 edge in interleague competition. It continued to dominate in the ensuing decade, as AL teams beat their NL rivals every season from 2004 to 2017. The senior circuit then reversed the trend in both 2018 and 2019, but at the start of 2020, the American League still held the edge, 3,166 to 2,898.
The following American League pitchers have homered in interleague play:
- Bobby Witt, 1997-06-30
- Dave Burba, 1998-06-07
- Dwight Gooden, 1999-06-11
- Esteban Yan, 2000-06-04
- Mark Hendrickson, 2003-06-21
- Jason Davis, 2004-06-20
- C.C. Sabathia, 2005-05-21
- Jason Johnson, 2005-06-08
- Zack Greinke, 2005-06-10
- Josh Beckett, 2006-05-20
- Kris Benson, 2006-06-17
- Jon Garland, 2006-06-18
- C.C. Sabathia, 2008-06-21
- Felix Hernandez, 2008-06-23
- Mark Buehrle, 2009-06-14
- Josh Beckett, 2009-06-14
- Zack Britton, 2011-07-03
- Nathan Karns, 2015-07-21
- Daniel Norris, 2015-08-19
- Anthony Ranaudo, 2016-07-28
No American League pitchers homered in interleague play in 2001, 2002, 2007, 2010, from 2012-2014 and from 2017 onward.
- Mark Feinsand: "Balanced schedule to bring more Interleague games", mlb.com, March 11, 2022. 
- Aria Gerson: "Happy birthday, interleague play! These are some of the best highlights from past 23 years", USA Today, June 12, 2020. 
- Gary Gillette and Pete Palmer: "Interleague Attendance Boost Mostly a Mirage", in The Baseball Research Journal, Society for American Baseball Research, Cleveland, OH, # 35 (2007), pp. 106-108.
- Manny Randhawa: "25 years on, the best Interleague moments", mlb.com, June 12, 2022.