We investigated the effect of antioxidant supplementation and repeated bouts of moderate intensity endurance exercise on markers of muscle damage (creatine kinase‐CK) and systemic inflammation (C‐reactive protein‐CRP). Following a placebo‐controlled, double‐blind, parallel, random design, 20 healthy, young, sedentary men performed two separate, but identical, bouts of cycling for 90 min at 65% VO2max. The first bout was after 8 days of supplementation with placebo (PL), whereas the second bout was after 8 days of supplementation with either PL (n = 10) or antioxidants (ANT, n = 10). Plasma was analyzed for CK and CRP at baseline, immediately post, 3 h post, and 24 h post exercise. Compared with baseline values, plasma CK was 2 fold higher at 3 h post exercise (P < 0.001) and 3.5 fold higher at 24 h post exercise (P < 0.001). Compared with PL, ANT had lower CK values at 3 h post (−31%, P = 0.079) and 24 h post (−34%, P < 0.001) exercise. A significant arm x exercise interaction (P = 0.004) indicated that 24 h post exercise values during the second bout of exercise were lower than during the first bout (−19%, P = 0.003). CRP at 24 h post exercise was 2.8–3.2 fold higher than all other values (P < 0.001), with no difference between the groups. We conclude that acute exercise increases plasma concentrations of both CK and CRP, and that only CK is attenuated with antioxidant supplementation. Antioxidant supplementation may reduce muscle damage in response to prolonged moderate intensity endurance exercise, but has no effect on the systemic inflammatory response. (Supported by NSERC Canada)