The Croatian suffered a broken nose in last week's Champions League defeat against Olympiacos and underwent surgery to repair the problem on Thursday.
The striker has since returned to training, but will not be fit for tomorrow's clash with Almeria.
"Mandzukic is the only real reference we have in attack because [Raul] Jimenez is more of a support striker. [Antoine] Griezmann and [Raul] Garcia are more similar positionally," Simeone told reporters.
"[Alessio] Cerci can do it but it's more likely he'd accompany someone there. It's hard to replace him because he's a fixture for us and gives us real presence in the box.
"We will have to have a lot of movement in midfield and the final third. And above all, we can't lose our reference up top. Those who play will have to play with presence in attacking areas."
Mandzukic is expected to return for this weekend's clash with Sevilla.