Osimhen made his comeback in Saturday's 2-1 win at Atalanta after a month out with a thigh injury but Mazzarri, who returned to the club for his second spell in charge this month, replacing Rudi Garcia, said he was still concerned about the Nigerian.
"Tomorrow I will talk to the doctors and Osimhen," Mazzarri told a press conference. "We will see if he will be able to do a quarter or a half. Such an important player should not be overloaded. We'll see whether to start him or bring him into the game."
Mazzarri said the Group C match in Madrid would be no easy task for Napoli after they lost 3-2 to Real in their last meeting in October.
"Tomorrow we have a very important head-to-head against one of the strongest teams in the world and we will see where we stand. In the meantime, let's start winning again," he said.
Mazzarri had words of praise for fellow Italian and Real manager Carlo Ancelotti and the side's midfielder Jude Bellingham.
"It is clear that Bellingham is phenomenal, he can become great. Ancelotti, he's the best, because he is the one who has won it all. But it's not me and him on the pitch; the teams will face each other and we'll see what happens.
"Real on paper are one of the strongest in the world. How do you put Real in difficulty? Tomorrow when we take the field we'll see."
Napoli are second in the group with seven points, five behind Real and four ahead of Braga, who host bottom side Union Berlin on Wednesday.
