The 37-year-old, who spent five years at Man City and made over 200 appearances between 2010 and 2015, joined Brighton in the summer on a free transfer from Liverpool.
Milner has featured six times for the Seagulls in all competitions so far this season, predominantly operating as a right-back, but he has missed each of the last five games due to a muscle injury.
However, De Zerbi has revealed that the experienced Englishman is "available to play" against Man City this weekend, although Brighton will be without four players for the trip to the Etihad.
Indeed, full-backs Tariq Lamptey and Pervis Estupinan have both been been ruled out due to injury, while Julio Enciso and Jakub Moder remain sidelined with long-term knee problems, but the latter is closing in on a return after taking part in training.
While Lamptey and Estupinan both missed the 2-2 draw with Liverpool before the international break, Moder has been sidelined with a troublesome ACL injury for the last 18 months.
Speaking at a press conference on Friday, De Zerbi said: "James Milner is available play, to start the game. Pervis Estupinan and Tariq Lamptey are injured. Jakub Moder has started to work with the group, which is great news for him."
On Moder, De Zerbi added: "When a player loses a year to injury, you need to think about human things. We want to help Jakub come back. I think he can become important for us.
"We play a lot of games after January and he can be a big player."
De Zerbi has also confirmed that Pascal Gross is fit and available for selection after representing Germany on international duty in friendlies with USA and Mexico; the 32-year-old managed to shake off a muscle issue shortly before the international break.
Brighton are seeking to end a four-game winless run in all competitions when they travel to the Etihad this weekend, but De Zerbi is expecting a "tough challenge" against the reigning Premier League champions Man City.
"It's very difficult preparing to play City. It's the toughest game and they want to keep the ball like us. It's a tough challenge," said De Zerbi.
Responding to the high praise received from Pep Guardiola, De Zerbi added: "Pep is the best coach in the world. He's a reference not only for me but for all coaches in the world and I'm happy when I hear him speak about me.
"It's an honour but we are not a big team yet. We have passion and we need to show a lot this season."
Brighton, who currently sit sixth in the Premier League table and two points behind Man City in third, have lost each of their last nine league visits to the Citizens, including a 3-1 defeat at the Etihad last season.