Objective: Adriamycin (ADR) is a potent and broad-spectrum antibiotic used in cancer treatments. However, the clinical efficacy of ADR is hampered by its dose-dependent cardiotoxicity. For this reason, in this study, it was aimed to examine the protective effect of Pleurotus eryngii extract (PEE) on the changes occurring in the heart tissues of rats treated with ADR. Methods: Sprague-Dawley male rats were divided into 4 equal groups (n = 6). DMSO/ethanol was given to control group by oral gavage. A single dose of 10 mg/kg ADR was administered to ADR group. After administration of 10 mg/kg single dose ADR, 200 mg/kg dose of PEE (dissolved in DMSO/ethanol) was given orally to ADR PEE group. 200 mg/kg PEE was administered by oral gavage to PEE group. At the end of the 21st day, the rats were decapitated. After decapitation, the heart tissues were removed and histological and quantitative RT-PCR analyzes were performed. Results: Inflammatory cell increase, loss of myofibril, cytoplasmic vacuolization, and vascular congestion were found in the heart tissues belonging to ADR group. PEE treatment caused improvement in these histopathological findings. Also, a significant increase in IL1-β immunoreactivity and IL1-β, BAX, Caspase-3 mRNA levels were observed in the ADR group compared to the control group. However, it was determined that significant decrease in IL-1β immunoreactivity and IL1-β, BAX, Caspase-3 mRNA levels in ADR PEE group compared to ADR group. Conclusion: PEE treatment has been shown to have a cardioprotective effect with anti-apoptotic and anti-inflammatory properties against ADR-induced cardiotoxicity.