© 2020 by the authors. Licensee MDPI, Basel, Switzerland.This study was performed to determine the effects of chitosan-coated nano-propolis (NP), which is synthesized via a green sonochemical method, and propolis on the side effects of cisplatin (CP), which is a widely used drug in the treatment of cancer. For this aim, 56 rats were divided into seven groups, balancing their body weights (BW). The study was designed as Control, CP (3 mg/kg BW at single dose of CP as intraperitoneal, ip), Propolis (100 mg/kg BW per day of propolis by gavage), NP-10 (10 mg/kg BW of NP per day by gavage), CP + Propolis (3 mg/kg BW of CP and 100 mg/kg BW of propolis), CP + NP-10 (3 mg/kg CP and 10 mg/kg BW of NP), and CP + NP-30 (3 mg/kg BW of CP and 30 mg/kg BW of NP). Propolis and NP (especially NP-30) were preserved via biochemical parameters, oxidative stress, and activation of apoptotic pathways (anti-apoptotic protein: Bcl-2 and pro-apoptotic protein: Bax) in liver and kidney tissues in the toxicity induced by CP. The NP were more effective than propolis at a dose of 30 mg/kg BW and had the potential to ameliorate CP’s negative effects while overcoming serious side effects such as liver and kidney damage.