The midfielder, starting his second game in six days, pulled up while off the ball and soon sat down on the pitch.
After talking to his team-mates, it was quickly decided that Maddison could not continue.
Conor Gallagher, former Blues player, was brought on as his replacement to a chorus of boos from the home side.
Sky Sports reported during the game that Maddison had suffered a groin injury.
It’s a huge blow for Spurs and Maddison, who was the standout performer against Coventry on Monday evening in his first first for 17 months by scoring a stunning opener from distance.
Maddison was a doubt heading into the derby at west London, having not been able to train in the three days after the game.
Roberto De Zerbi played down the chances of a Maddison start at his pre-match press conference on Friday, only for the England man to get the nod on Saturday evening.
Maddison impressed in the first half at Stamford Bridge, but was forced off with less than four minutes of the second half played.