Introduction: Cognitive impairment and glucose intolerance are prevalent in obese subjects. Irisin, a recently identified modifier of cognitive functions and glucose metabolism, was reported to be induced by physical exercise. We examined the association of exerciseinduced irisin levels with improved cognitive functions and glucose metabolism in both obese and normal weight subjects. Subjects and Methods: 120 subjects, both males and females, comprised of 60 obese and 60 normal-weight subjects were undergone supervised active aerobic exercises for 3-months. Irisin levels, cognitive functions, fasting blood glucose, insulin, homeostatic model assessment of insulin resistance index (HOMA-IR) were assessed at the initiation and termination of the study. Results: Obese subjects demonstrated lower irisin levels, impaired cognitive functions and higher insulin as well as HOMA-IR levels compared to the normal weight group. Physical exercise induced significant upregulation of irisin levels together with improvement of cognitive functions and significant reduction of insulin and HOMA-IR levels in both groups. Exercise-induced irisin levels demonstrated significant positive correlations with improved cognitive functions and significant negative correlation with insulin level and HOMA-IR. Conclusion: Physical exercise improves cognitive functions and glucose metabolism. Our results suggest that irisin could be an important molecular mediator and therapeutic target for improving cognitive functions and glucose metabolism.