Although chemotherapy is one of the pillars in cancer treatment, its side effects have extremely harmful impacts on many of the body's organs. This study investigates the potential protective effect of the natural product, Biobran/MGN-3, (also known as Lentin Plus 1000), against kidney damage and immune modulation caused by the chemotherapeutic agent Etoposide in rats. Etoposide impairs kidney function, demonstrated by high levels of urea, and imbalances in electrolytes Na and K, and low calcium levels. Etoposide also increased parameters reflecting oxidative stress, malondialdehyde (MDA) and nitric oxide (NO), while reduced the enzyme-mediated antioxidant defense activity, Glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Immunostaining of kidney tissues revealed that Etoposide caused inflammation by increasing proinflammatory cytokines IL-1β, TNF-α, and TGF-β expression. In addition, it increased apoptosis by raising levels of Bax, Caspase-3, and Cytochrome C, which was evident by qPCR. Comet assay revealed DNA damage in kidney cells following Etoposide treatment. It was evident by flow cytometry that Etoposide increased CD8, CD4, CD3, and CD19, which indicates lymphocyte infiltration into the kidney. On the other hand, Biobran/MGN-3 helped protect kidney function, lowering oxidative stress, restoring antioxidant enzyme activity, and reducing pro-inflammatory substances. Biobran/MGN-3 also counteracted the Etoposide-induced increase in Bax, Caspase-3, and Cytochrome C, lowering the cell death rate in the kidneys. Additionally, the results showed that Biobran/MGN-3 adjusted immune cell levels by increasing CD8+, CD4+, CD3+, and CD19+ cells, boosting both T-cell and B-cell activity. These findings suggest that Biobran/MGN-3 could be a helpful treatment addition to reduce kidney damage and mitigate immune impairment from Etoposide.