The high forces undergone during repetitive eccentric, or lengthening, contractions place skeletal muscle under considerable stress, in particular if unaccustomed. Although muscle is highly adaptive, the responses to stress may not be optimally regulated by the body. Reactive oxygen species (ROS) are one component of the stress response that may contribute to muscle damage after eccentric exercise. Antioxidants may in turn scavenge ROS, thereby preventing or attenuating muscle damage. The antioxidant vitamins C (ascorbic acid) and E (tocopherol) are among the most commonly used sport supplements, and are often taken in large doses by athletes and other sportspersons because of their potential protective effect against muscle damage. This review assesses studies that have investigated the effects of these two antioxidants, alone or in combination, on muscle damage and oxidative stress. Studies have used a variety of supplementation strategies, with variations in dosage, timing and duration of supplementation. Although there is some evidence to show that both antioxidants can reduce indices of oxidative stress, there is little evidence to support a role for vitamin C and/or vitamin E in protecting against muscle damage. Indeed, antioxidant supplementation may actually interfere with the cellular signalling functions of ROS, thereby adversely affecting muscle performance. Furthermore, recent studies have cast doubt on the benign effects of long-term, high-dosage antioxidant supplementation. High doses of vitamin E, in particular, may increase all-cause mortality. Although some equivocation remains in the extant literature regarding the beneficial effects of antioxidant vitamin supplementation on muscle damage, there is little evidence to support such a role. Since the potential for long-term harm does exist, the casual use of high doses of antioxidants by athletes and others should perhaps be curtailed.