Caffeine supplementation can modulate oxidative responses caused by metabolic and oxidative stress during high-intensity handball competitions by optimising oxidative-antioxidant and enhancing the activity of antioxidant defence enzymes, and facilitate the improvement of performance and physiological recovery of professional athletes. The aim of this study was to investigate the effect of caffeine supplementation on oxidative responses and physiological performance of professional handball players under stress conditions caused by high-intensity competitions. This quasi-experimental study was conducted with the participation of 14 male professional handball players aged 8 to 23 years who were randomly divided into two groups of caffeine supplementation (6 mg/kg of body weight) and placebo; after four weeks of supplementation, blood samples were collected before and after the official Premier League match and data were analysed with dependent and independent t-tests. In the caffeine supplement group, MDA levels decreased significantly after the competition (P<0.05), while in the placebo group did not change. The activities of SOD and GPx enzymes increased significantly after the competition in the caffeine group (P<0.05), but no significant difference was observed in the placebo group. Also, CAT activity increased significantly after the competition in the caffeine group (P=0.027) and the post-test CAT level in this group was significantly higher than in the placebo group (P=0.027), while the placebo group did not change significantly (P=0.52). It can be concluded that caffeine supplementation can prevent oxidative stress-related damage during intense sports competitions by strengthening the body’s antioxidant defence mechanisms and help improve the performance and recovery of athletes.