The will be played on June 29-30 at London Stadium, the site of the 2012 Olympic Games.
The MLB is the third major US league to cross the Atlantic, with the National Basketball Association and NFL having already established themselves in London.
The rivalry between two of the sport's most successful teams stretches back more than a century and is widely regarded as the most passionate in baseball.
There is no better way to start the London Series and the first Major League Baseball fixture in Europe than a clash between two heavyweights of worldwide sport - the New York Yankees and the Boston Red Sox.
Major League Baseball commissioner Rob Manfred was in London to make the announcement and said there was a commitment to play in London in 2020 as well, with the "intention to establish a long-term footprint in the city".
The United Kingdom will follow other worldwide venues that have hosted regular season Major League games, joining Mexico, Japan, Puerto Rico and Australia. "So fans can expect intense competition during what will surely be a great few days in London".
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"They are excited about the chance to meet new fans and showcase the game they love", he said.
Mr Khan has said he wants to make London the sporting capital of the world.
London has oftentimes played host to middling or low-level teams for its NFL and NBA games, but MLB appears to be going all in by showcasing its premier rivalry in the form of the Yankees against the Red Sox.
Red Sox pitcher Joe Kelly connects with a punch on the head of Yankees' Tyler Austin. "I can't wait to hear someone shout "play ball" at London Stadium", he added.
The Boston Red Sox World Series win in 2004 ended an 86-year title drought, burying the "Curse of the Bambino", the supposed hoodoo stemming from the Red Sox trading beloved star Babe Ruth to the Yankees.
The NFL have been playing regular-season games in London since 2007, and could eventually host a franchise if the proposed purchase of Wembley Stadium by Shahid Khan, the owner of Jacksonville Jaguars, goes ahead.
The NBA and National Hockey League have also held regular-season games in London.