The top-flight giants will contest a match to honour the opening of St. Louis' Busch Stadium on May 23, with both sides having travelled stateside for pre-season tours in recent years.
"The summer visit to St Louis is tremendously exciting for us," City chief executive Ferran Soriano said on the club's official website.
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"You will now find Manchester City soccer fields in some of the most deserving communities of New York, Miami, LA and Chicago, and loyal supporters clubs in major cities across the continent."
The Blues travelled over the Atlantic last season to face the MLS All-Star team, and chief executive Ron Gourlay is happy to have a competitive match after the campaign, as well as the commercial boost that Chelsea will receive.
"It's an excellent opportunity for the club to be able to return to America so quickly after our successful tour there last July," Gourlay said on the club's official website.
"The club and the players have enjoyed regularly traveling to the U.S. and also helping to create long-term growth and sustainability of soccer in the country through our super club network.
"We will face the strongest opposition in Manchester City, and I am sure we will provide a competitive and entertaining match in St Louis."