Although a physiological dose of testosterone replacement therapy (p-TRT) has been shown to improve left ventricular (LV) function, some studies reported that it increased the risk of myocardial infarction in testosterone-deprived men. We previously reported that vildagliptin might be used as an alternative to the p-TRT. In this study, we hypothesized that a combined low-dose TRT with vildagliptin exerts greater efficacy than single regimen in improving cardiometabolic function in obese-insulin resistant rats with testosterone deprivation. Male rats were fed on a normal diet or high-fat diet for 12 weeks. Then, they were divided into 2 subgroups; sham operation and orchiectomy (NDO, HFO) and fed their diets for another 12 weeks. At week 25, orchiectomized rats were subdivided into 4 groups, vehicle, p-TRT, vildagliptin, and combined drugs. At week 29, cardiometabolic and biochemical parameters were determined. HFO rats had obese-insulin resistance with a worse LV dysfunction, compared with sham. Vildagliptin and combined drugs effectively reduced insulin resistance. All treatments reduced blood pressure, cardiac autonomic imbalance, LV dysfunction, mitochondrial dysfunction, apoptosis, and increased mitochondrial fusion in NDO and HFO rats. However, p-TRT and combined drugs, but not vildagliptin, reduced mitochondrial fission in NDO and HFO rats. We concluded that combined low-dose TRT with vildagliptin mitigated LV function at a similar level to the p-TRT alone and vildagliptin via improving mitochondrial fusion, reducing mitochondrial dysfunction and apoptosis in testosterone-deprived rats. Our findings suggest that low-dose TRT combined with vildagliptin may be an alternative for p-TRT in conditions of obese-insulin resistance with testosterone deprivation.