OBJECTIVES: We aimed to determine the effects of adipose-derived mesenchymal stem cells (AD-MSCs) and melatonin on the kidney in rats with ischemia-reperfusion injury. METHODS: Sixty male rats were divided into six groups: Control group (C) (n: 10), Sham group (S) (n: 10), Ischemia Reperfusion group (IR) (n: 10), Group that was treated with melatonin intraperitoneally after ischemia reperfusion (IR+M) (n: 10), Group in which AD-MSCs were applied locally after ischemia reperfusion (IR+MSC) (n: 10), and group that after IR, melatonin and AD-MSCs were administered (IR+MSC+M) (n: 10). Five rats from each group were sacrificed on day 3 and five of them on day 14. Blood samples were analyzed for BUN and creatinine. Histological analysis was performed. RESULTS: BUN and creatinine levels were higher in the IR group compared to the groups (p < 0.05). There was a statistically significant decrease in creatinine levels in the IR+MSC+M group on day 14. BUN levels decreased significantly in the M and IR+MSC+M groups (p < 0.05). Losses in the glomerular epithelium and tubule cells, enlargement, and hemorrhage areas in the bowman space were detected in the IR group. The histologic scoring was significantly lower in the IR+MSC+M group on the 14th day (p < 0.05). While Caspase-3 and Bax expression increased in the IR group, it decreased in the treatment group, especially on day 14 (p < 0.05). Bcl-2 expression was negative in all structures in the IR group, whereas it was increased in the treatment groups. The apoptosis rate was highest in the IR group and decreased in the treatment groups (p < 0.05). CONCLUSIONS: Melatonin and MSC were effective in ischemia-reperfusion injury by improving renal function and inducing the anti-apoptotic pathway.