Background: Studies have shown that exercise and insulin can improve cognitive function. However, little is known about the combined effects of insulin and exercise on memory and learning under stress conditions. Objectives: This study was designed to investigate the effects of peripheral insulin injection and/or physical exercise on stressinduced memory deficit. Methods: Adult male Wistar rats (200-220 g) received immobilization stress (2 h/d × 7 d), mild-intensity exercise (30 min/d × 7 d), intraperitoneal (i.p.) injection of insulin (1, 6, 12 IU/kg) or saline, insulin-exercise treatment, or no intervention. The animals were assigned on a random basis to 21 experimental groups (N = 10). They were trained and tested in the Morris water maze. Results: Chronic restraint stress impaired spatial performance in the Morris water maze (P < 0.05) and elevated serum corticosterone levels (P < 0.001). Detrimental effects of stress were alleviated by exercise (P < 0.01). The lower dose (1 IU/kg) of insulin protected the animals against the deleterious effects of stress. The combined effects of exercise and insulin (low and moderate doses) prevented stress-induced learning and memory impairment. Conclusions: Insulin and/or exercise can prevent stress-induced memory deficits. The cognitive benefits of exercise continue to evolve after cessation of treatment. Insulin-exercise treatment is as effective as exercise alone and insulin alone for preventing the detrimental effects of stress.