In‐vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans has yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double‐blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested 2 capsules/day that each contained 500 mg of L‐ascorbic acid and 450 international units (IU) of dl‐α‐tocopherol acetate for eight weeks. The placebo group ingested capsules of identical external appearance, taste, and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre‐supplementation (normoxia), post‐supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation [electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A• −)] increased during hypoxia (15,152 ± 1,193 AU vs. 14,076 ± 810 AU at rest, P < 0.05) and was further compounded by exercise (16,569 ± 1,616 AU vs. rest, P < 0.05), responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation as measured by thrombin‐antithrombin complex, at rest in normoxia (28.7 ± 6.4 ug mL−1 vs. 4.3 ± 0.2 ug mL−1 pre‐intervention, P < 0.05) and was restored but only in the face of prevailing oxidation. Collectively, these findings are the first to suggest that human free radical formation likely reflects an adaptive response that serves to maintain vascular haemostasis.