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Although cisplatin is used as a first-line therapy in many cancers, its nephrotoxicity remains a real problem. Acute kidney injuries induced by cisplatin can cause proximal tubular necrosis, possibly leading to interstitial fibrosis, chronic dysfunction, and finally to a cessation of chemotherapy. There are only a few nephroprotective actions that can help reduce cisplatin nephrotoxicity. This study aims to identify new prophylactic properties with respect to medicinal mushrooms. Among five <i>Ganoderma</i> species, the methanolic extracts of <i>Ganoderma tuberculosum</i> Murill., <i>Ganoderma parvigibbosum</i> Welti & Courtec. (10 µg/mL), and their association (5 + 5 µg/mL) were selected to study respective in vitro effects on human proximal tubular cells (HK-2) intoxicated by cisplatin. Measurements were performed after a pretreatment of 1 h with the extracts before adding cisplatin (20 µM). A viability assay, antioxidant activity, intracytoplasmic β-catenin, calcium, caspase-3, p53, cytochrome C, IL-6, NFκB, membranous KIM-1, and ROS overproduction were studied. Tests showed that both methanolic extracts and their association prevented a loss of viability, apoptosis, and its signaling pathway. <i>G. parvigibbosum</i> and the association prevented an increase in intracytoplasmic β-catenin. <i>G. parvigibbosum</i> prevented ROS overproduction and exhibited scavenger activity. None of the extracts could interfere with pro-inflammatory markers or calcium homeostasis. Our in vitro data demonstrate that these mushroom extracts have interesting nephroprotective properties. Finally, the chemical content was investigated through a phytochemical screening, and the determination of the total phenolic and triterpenoid content. Further studies about the chemical composition need to be conducted.