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. The player will undergo scans on Sunday.
Asked for an update after the game, De Zerbi told reporters: “Not very important problem I hope. We need to make the medical check tomorrow.
“I hope it's not a big problem because he's a special player for us. We need him.”
De Zerbi was more positive when speaking to BBC Sport, adding: "I think it is not a big problem. We have to see."
"He played very well while he was on the pitch then Gallagher played with different characteristics,” he added. “Different style but he played very well.
"James is a different player. He feels football, he understands football. It is easier for me when you have a player of his talent.”
"Anyone who loves football, loves James Maddison,” De Zerbi told Sky Sports. “He is a special player.
“I said in the dressing room James let me know the problem because we need you. Gallagher played well when he came into the side, we have many, many great players.
"It depends on his physical condition. Maddison is an unbelievable player."