Objectives: Sodium/glucose co-transporter-2 inhibitor (SGLT2i) or dipeptidyl peptidase IV inhibitor (DPP4i) are newer anti-diabetic drugs in type II diabetes mellitus (DM), but their use in tacrolimus (TAC)-induced DM is still undetermined.  Methods: We performed this study to evaluate the effect of these two drugs in TAC-induced DM and nephrotoxicity in ex vivo and in vivo. Results: In experimental Sprague Dawley rat model of TAC-induced DM and nephrotoxicity, dual inhibition of DPP4 and SGLT2 significantly decreased blood glucose level, HbA1C and increased plasma insulin levels and pancreatic islet size compared with each drug. In kidney, dual inhibition improved renal function decreased interstitial fibrosis and profibrotic cytokines compared with DPP4i and SGLT2i alone. Increased oxidative stress by TAC was remarkably decreased with DPP4i or SGLT2i in serum, pancreatic and renal tissues, and this decrease was much significant in the combination group. In in vitro study, TAC decreased the cell viability of human kidney-2(HK-2) cells and insulin-secreting beta-cell-derived line(INS-1) cells. SGLT2i protected TAC-induced cell death in HK-2 cells, but not in INS-1 cells.  Conclusions: Addition of DPP4i to SGLT2i compensated a lack of protective effect of SGLT2i on INS-1 cells. This finding provides the rationale for combined treatment of SGLG2i and DPP4i in TAC-induced DM and nephrotoxicity.