The Naples outfit travel to Stamford Bridge on Wednesday holding a 3-1 advantage from the first leg of their last-16 tie.
Goran Pandev will replace Cavani, who is the team's top scorer with 16 league goals, and play alongside Ezequiel Lavezzi in Napoli's attack.
"I needed to rest someone," Mazzarri said. "I expect Edinson to be very important for us in our next games but he will rest tomorrow [Friday]."
Mazzarri is focused on the task at hand and has warned his players there is no room for complacency, despite his side having won their last four league games.
"We face a very difficult game," he said. "Cagliari have lost their last two league games and they will be eager to return to victory.
"We have to be extremely concentrated and have a good performance against Cagliari in order to take maximum points."
Last weekend's 2-1 triumph at Parma lifted Napoli to fifth place, five points behind Lazio who hold the last Champions League qualifying spot.
Rivals Cagliari have suffered a recent drop in form which has seen them plummet to 15th place.
The Sardinians lost 3-0 at Siena last time out to suffer their second straight defeat.
"We cannot let our guard down," Cagliari coach Davide Ballardini said. "I am very disappointed with the team's performance at Siena.
"Against Napoli, I want to see this Cagliari team playing at the level they were playing earlier in the season."
Cagliari have scored one goal in their last three league games while they have conceded five times in as many fixtures.