PurposeCisplatin-based chemotherapy is now an important treatment for improving bladder cancer prognosis. However, challenges in clinical treatment remain due to the numerous side effects of chemotherapy. Natural killer (NK) cells regulate certain immune responses and play a significant role in tumor surveillance and control. The efficacy of NK cells combined with cisplatin for chemoimmunotherapy in bladder cancer remains poorly understood.MethodsIn this study, we established an MB49 tumor-bearing mouse model, tumor growth was measured in a control group and in groups treated with cisplatin, NK cells or both. Organ indices, biochemical indicators of blood serum, and expression of apoptotic proteins were used to assess the extent of organ damage. ELISA and immunohistochemistry were used to analyze the levels of immune cells and cytokine expression in serum, spleen, and tumor tissue.ResultsNK cells combined with cisplatin exhibited better antitumor activity. NK cells also alleviated the organ damage caused by cisplatin and improved the survival rate. Treatment with NK cells increased the expression of IL-2 and IFN-γ as well as the number of CD4 + T cells. Additionally, cisplatin increased the expression of natural killer group 2, member D (NKG2D) ligands thus activating NK cells to kill tumor cells.ConclusionNK cells could alleviate the side effects of cisplatin treatment and enhance antitumor activity. The combination of NK cells and cisplatin thus provides a promising option for chemoimmunotherapy for bladder cancer.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11255-023-03650-w.