Daily exposure to solar light is not so harmless as previously thought, since UVA and UVB radiation has a significant effect on human health, by inducing skin-related inflammatory manifestations, such as hyperpigmentation, dermatitis, premature aging, erythema, and sunburn, among the most common skin conditions. At the same time, irreversible diseases such as various types of skin cancers, like basal cell carcinoma, melanoma, and squamous cell carcinoma, have begun to increase at dramatic rates, due to inflammatory and oxidative malignant effects of UV radiation exposure. Within this article, the health promoting effects of sunscreen for skin protection and especially of sunscreen enriched with natural antioxidant, anti-inflammatory, anti-allergic, and anti-cancer bio-functional ingredients are thoroughly reviewed. Emphasis is given to bioactives from grape by-products, such as bio-functional phytochemicals like flavonoids, stilbenes, and phenolic acids, as well as to tomato-derived bioactives like lycopene, which act either solely or synergistically and significantly enhance the antioxidant capacity of the composition product, as well as its photo-protection. The promising outcomes from in vitro studies and those reported from in vivo approaches, as well as the mechanisms of the obtained antioxidant, anti-inflammatory, anti-thrombotic, and antitumor action(s) of sunscreens infused with such natural bioactives, are also outlined. Limitations, such as the difficulties in incorporating lipophilic compounds like lycopene and/or amphiphilic phenolics into sunscreen cosmetic formulations, as well as future perspectives on the overall benefits that these compounds give to sunscreens, helping to improve properties such as smell, color, homogeneity, water resistance, and especially the Sun Protection Factor (SPF), are also discussed.