The Italian has four changes to the team beaten 2-1 at Man City.
Ansu Fati, Billy Gilmour, Joel Veltman and Jan Paul van Hecke start, with Igor Julio and Carlos Baleba dropping to the bench.
Danny Welbeck and Solly March both miss out after suffering injuries at the Etihad. The latter was covering the left-back role due to Pervis Estupinan’s injury, which left De Zerbi with a selection headache.
He has ultimately chosen veteran James Milner as his latest emergency left-back. The former Liverpool man was substituted at half-time against City – another one of his former employers – at the weekend.
Brighton have taken just one point from their opening two games in Group B ahead of the double-header with the Dutch giants.
Asked if the game at the Amex was a must-win, De Zerbi replied: “Every game we have to try to win. Don’t play only for the result. We have to play showing our quality.”
Brighton though suffered a big blow with the news that Solly March is set for a ‘long period’ out of the side. The winger suffered a knee injury and looks set to be out for months.
Speaking at a press conference ahead of Thursday’s Europa League clash with Ajax, De Zerbi said: “Solly March’s injured, Danny Welbeck as well. We have enough to play and win the game.
“Solly unfortunately is a very, very tough injury, a very important injury. We lose him for a long period and for Welbeck the same."
Meanwhile, European heavyweights Ajax have had a wretched start to the season, with head coach Maurice Steijn losing his job after the 4-3 loss at Utrecht – which left them second bottom of the Eredivisie.
"Ajax are in not a very good moment but they are still Ajax," De Zerbi said.
"The history of the club is incredible and unbelievable, and we expect a lot from them.
"But we are Brighton and when we play in a good way, what we're able to do, I think we have a chance to win the game."
Brighton XI: Steele, Veltman, van Hecke, Dunk, Milner, Gilmour, Gross, Adingra, Joao Pedro, Mitoma, Fati.
Subs: Verbruggen, McGill, Igor, Webster, Dahoud, Lallana, Baleba, Ferguson, Buonanotte, Hinshelwood, Duffus
Ajax XI: Ramaj, Gaaei, Sutalo, Hato, Sosa, Tahirovic, Berghuis, Taylor, Borges, Brobbey, Bergwijn.
Subs: Akpom, Saleh-Eddine, Medic, van den Boomen, Pasveer, Vos, Avila, Hlynsson, Godts, Gooijer, Setford.