Edin Dzeko's second goal of the game tied it in the 85th minute for Man City and Micah Richards scored the stoppage-time winner by redirecting a header into the net.
In a game played before a standing-room crowd of 48,623 at the St. Louis Cardinals' Busch Stadium, Juan Mata set up a pair of first-half goals for Chelsea against the general run of play.
Mata's cross set up Demba Ba's header for the lead in the 15th minute and Cesar Azpilicueta converted a penalty shot after Mata was dragged down by Karim Rekik.
Manchester City scored through Javi Garcia and Dzeko in a 3-minute span of the second half not long after Chelsea had substituted first-choice goalkeeper Petr Cech and brought on Jamal Blackman, and the two late goals sealed the win.
There will be a second match between the two at New York's Yankee Stadium.
Frank Lampard did not play for Manchester and the club's leading career scorer also is skipping the second friendly to join England. Defenders Gary Cahill and Ashley Cole also are heading back home early.
Manchester City beat Chelsea 4-3 in U.S. friendly
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