The increasing rate of obesity in the past years has become a worldwide concern and it causes many diseases. Even though, Orlistat, a synthetic anti-obesity drug approved by FDA, it causes severe side effects. DATS, a natural product from garlic have gained attention in many biological activities. The aim of the study is to determine the impact of Dially trisulpide (DATS) and its combination with Orlistat therapy on obese animals. 30 male Wistar rats (150–180g) were assigned into 5 groups (n=6). Group 1 rats received normal diet and Group 2 fed with high fat diet (HFD) for 14 weeks. Group 3–5 animals fed with HFD for 8 weeks, after that respective drugs were given simultaneously along with HFD for 6 weeks; Group 3: HFD+Orlistat; Group 4: HFD+DATS; Group 5: HFD+Orlistat+DATS. Before and after drug treatment, body weight was measured and blood was collected for assessment of lipid and liver function profiles. After end of the treatment 14 weeks, liver and adipose tissues were collected for antioxidants determination and histological observations. The significantly (p<0.05) increased body weight, serum glucose, total cholesterol, triglycerides, LDL-cholesterol were observed while significantly (p<0.05) decreased HDL-cholesterol and liver function parameters in HFD induced rats when compared to control group. The significantly (p<0.05) decreased activities of SOD, CAT, GPx and GSH levels were observed while significantly (p<0.05) increased LPO in both the tissues of HFD treated group when compared to control. Histopathological changes were observed in both the liver and adipose tissue of HFD treated group. The DATS and its combination with orlistat supplementation restored all the parameters significantly (p<0.05) especially liver function parameters and also retrieved histopathological changes when compared to orlistat alone. DATS and its combination with Orlistat had great effect than Orlistat alone.