Doxorubicin (DOX) is one of the most commonly used antineoplastic agents; however, its considerable nephrotoxicity restricts its clinical use. Kaempferol (KPF), a naturally-occurring flavonoid, possesses various biological benefits, including anti-tumor activity that has garnered increasing attention. This study aimed to evaluate the possible reno-protective role of KPF in DOX nephrotoxicity. Male BALB/c mice were injected with DOX via the tail vein to imitate renal damage. Their body and kidney were weighed after 2 weeks of KPF therapy, and urine, serum, and tissue samples were obtained to establish proteinuria, serum creatinine, and pathological alterations. The variations in SOD, GSH, CTA, MDA, and SOD2 expression in renal tissues were measured, and p-ASK1, p-p38, and P-JNK were evaluated by western blot. Cell viability was detected using MTT tests. Apoptosis was assessed by TUNEL, Hoechst 33342, PI staining, and western blot. Fluorescent ROS probes were used to assess oxidative cell damage. KPF ameliorated DOX-induced renal injury, improved proteinuria and renal function, restored GSH content, SOD activity and CTA activity in kidneys, inhibited the overproduction of MDA, and suppressed DOX-induced activation of the MAPK signaling pathway. In NRK-52E cells, KPF significantly inhibited DOX-induced ROS overproduction, restrained the activation of MAPK signaling pathway, and alleviated DOX-induced cell morphological damage and loss of cell viability, While it did not affect the toxicity of DOX to 4T1 cells. KPF provides a protective effect against DOX-induced nephrotoxicity while maintaining the cytotoxicity of DOX in breast cancer cells, thereby it may provide a viable solution to lessen renal toxicity in cancer patients receiving DOX.