Irisin is a myokine secreted from muscle cells and other organs and it has multiple endocrinal effects on other body systems. The exact relationship of irisin in diabetes and obesity is still not completely understood. Aim of the work: Is to study the effect of exogenous and endogenous irisin on obesity and type II diabetes mellitus in male albino rats. Methods: 90 male albino rats divided into 3 groups. Control group;10 rats that fed with a regular diet. Obese group; 40 rats that fed with high fat diet for 8 weeks then subdivided into 4 equal groups 10 rats each. Control obese group; treated by intraperitoneal (ip) injection of 150 μl saline daily for 8 weeks. Irisin treated obese group;treated by ip injection of 150 μl of prepared irisin solution daily for 8 weeks. Exercise treated obese group;treated by moderate intensity swimming exercise for 30 min per day 5 days a week for 8 successive weeks. Irisin and exercise treated obese group;treated as before. Diabetic group; 40 rats that fed with high fat diet for 4 weeks then injected with a single ip streptozotocin (STZ) in a dose of 30 mg/kg body weight. After one week, diabetic group subdivided into 4 equal groups 10 rats each. Control diabetic group, irisin treated diabetic group, exercise treated diabetic group and irisin and exercise treated diabetic group;treated as before. Results:Non treated obese and diabetic groups showed significant increase in body weight gain, body mass index, serum insulin level, fasting glucose level,(HOMA-IR), osteopontin level, triglycerides level and atherogenic index of plasma.While, showed significant decrease in serum nitrite/ nitrate level,HDL cholesterol level,irisin level and (HOMA-S) when compared to the control group.In contrast, irisin treated obese and diabetic groups showed significant decrease in body weight gain, body mass index, serum insulin level, fasting glucose level,(HOMA-IR), osteopontin level, triglycerides level and atherogenic index of plasma. Whileit showed significant increase in serum nitrite/ nitrate level, HDL cholesterol level, irisin level and (HOMA-S) when compared to the control obese and control diabetic groups respectively.Treated obese and diabetic groups by moderate intensity swimming exercise for 8 successive weeks showed; significant changes in all parameters as compared to control obese and control diabetic groups respectively and insignificant changes in all parameters as compared to irisin treated groups.Combination of irisin and exercise treated obese and diabetic groups showed insignificant change compared to control group and a significant change compared to either irisin treated groups or exercise treated groups. except in body weight gain and body mass index there is no significant difference as compared to control group. Our work also showed that; serum irisin level is negatively correlated with all studied parameters except; insulin sensitivity, serum HDL cholesterol level and serum nitrite/nitrate level is positively correlated.We can conclude that combination therapy of irisin and exercise produce better results as anti hyperglycemic, anti-hyperlipidemic and , antioxidant.