Ultraviolet (UV) radiation-induced oxidative stress may result in acute and chronic photodamage. Based on the endogenous antioxidant system, the administration of antioxidants for scavenging reactive oxygen species might be a promising strategy in the prevention of UV-induced skin reactions. The relevance of the most common antioxidants, vitamins E and C, is reviewed focusing on topical and systemic photoprotective effects in animals and humans. Topically applied vitamin C induced significant photoprotective effects at concentrations of at least 10% in animals and humans, whereas a photoprotective effect has not been demonstrated by oral administration even at high doses in humans. Topical vitamin E reduced erythema, sunburn cells, chronic UV-B-induced skin damage, and photocarcinogenesis in the majority of the published studies, whereas only high doses of oral vitamin E may affect the response to UV-B in humans. Combination of vitamins C and E, partly with other photoprotective compounds, did increase the photoprotective effects dramatically compared to monotherapies. This synergistic interplay of several antioxidants should be taken into consideration in future research on cutaneous photoprotection.