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The 18-year-old has been in great form for Barca this term, scoring five goals and assisting two more in 10 appearances in all competitions.
That was one of four caps earned under Luis Enrique and the former Barcelona coach is confident the teenage attacker will find his best form once he returns to action.
"Regardless of how old you are, injuries are part of football," Luis Enrique said at a news conference ahead of Wednesday's friendly with the Netherlands.
"It is a sad moment but he will overcome it. He will be the old Ansu again."
Fati's absence could give the likes of Alvaro Morata and Marcos Llorente a chance to shine in attack against the Netherlands.
Atletico Madrid midfielder Koke is back with Spain for the first time in over two years, while team-mate Llorente is in line for his maiden cap this international window.
"Morata is here because he has the confidence of his coach. He has a strong profile," Luis Enrique said.
"Llorente is almost already playing as a forward at Atletico now as the second striker.
"The normal thing is to change your position, becoming deeper in your role, but with Llorente it is the other way around."
Spain enter the midweek friendly in Amsterdam on the back of a surprise 1-0 Nations League loss to Ukraine last month.
La Roja have won only two of their five matches this calendar year but Luis Enrique insisted all that matters is that his side peak in time for next year's rescheduled Euro 2020 finals.
"These games will help us to see all the players," he said. "But after playing these three games we still won't know what we have for the European Championships.