Mitoma, who has played 24 matches this season, limped off with an ankle injury late in the second half of Brighton's 1-1 draw at Crystal Palace last week. The 26-year-old left Selhurst Park on crutches and wore a protective boot.
The Asian Cup kicks off on Jan. 12 in Qatar with Japan playing their first group game against Vietnam two days later.
"Tomorrow (Thursday), we have more or less 10 injured players, maybe less, maybe eight, but two players can't start the game," De Zerbi said ahead of Thursday's home match against fourth-placed Tottenham Hotspur.
"We've lost Kaoru for around six weeks. Four, five or six weeks. I don't think he can play in the Asian Cup with Japan.
"(Pervis) Estupinan is available for the bench."
While left back Estupinan's return gives Brighton a boost, they still have Ansu Fati, Solly March, Julio Enciso, Adam Webster, Tariq Lamptey and Joel Veltman out injured.