Abstract Background: Exercise may encourage myokines secretion such as irisin. Irisin is one of the myocytokines that is related to energy homeostasis and obesity. Aim of Study: Study the effect of irisin and/or moderate intensity swimming exercise on metabolic homeostasis in high fat induced obesity in male albino rats. Material and Methods: The present work will be carried out on 50 male albino rats, they were divided into 2 groups I: Control group 10 rats fed with normal diet and intraperitoneal injected with 150ml saline daily for 8 weeks II: Obese group 40 rats were fed with high fat diet they are subdivided into 4 subgroups 10 rats each IIa. Control obese IIb. Irisin treated Obese these rats are intraperitoneal injected with irisin in a dose of 100ng/ml per day for 8 weeks IIc. Exercise treated Obese the exercise groups will swim for 30min a day, 5 days a week for 8 successive weeks IId. Irisin and exercise treated obese group rats will be treated as subgroup b and c. At the end of the experimental period, the following parameters were measured for all animals: Body Weight (BW), Body Mass Index (BMI), abdominal circumference. Blood samples were obtained to measure serum insulin, fasting blood glucose, calculate Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and, Homeostatic Model Assessment of Insulin Sensitivity (HOMA-S), measure serum Irisin, osteopontin, Total Cholesterol (TC), LDL cholesterol level, HDL cholesterol level, Triglycerides (TG), Free Fatty Acids (FFA), Nitrite/Nitrate and Malondialdehyde (MDA). Results: Final BW in irisin and/or exercise animals are significantly decreased as compared to final BW of control obese group. Animal treated with Irisin and exercise shows insignificant change as compared to final BW in normal control group. BMI, abdominal circumpherence, serum insulin, fasting glucose, Homa IR, osteopontin, TC, LDL, TG, FFA, MDA are significantly increased in obese rats as compared to normal control, either Irisin injection or exercise results in significant decrease in all these parameters, when Irisin injection is combined with exercise it causes significant decrease when compared to control obese and insignificant difference with normal control group. As regard Irisin level, HOMA insulin sensitivity, HDL and Nitrite/Nitrate they are significantly decreased in obese rats as compared to normal control, either irisin injection or exercise results in significant increase in these parameters, if Irisin injection is combined with exercise it causes significant increase in these parameters reaching the normal control level. Conclusion: Irisin and/or moderate intensity swimming exercise initiate a novel strategy for the treatment of obesity also the potential use of irisin as a predictive marker for insulin resistance has a therapeutic potential in obese rats.