Background: Exposure to solar UV rays has deleterious effects on skin appearance through physiological and structural alterations that eventually lead to skin photo-damage. Aims: To test the photo-protective effect of a novel preparation, Dead Sea Osmoter Concentrate (DSOC), containing high concentration of Dead Sea water. Methods: Human skin organ culture was used as a model to assess the biological effects of UVB irradiation and the protective effect of topical application of DSOC preparation. Skin pieces were analyzed for mitochondrial activity by Alamar blue (resazurin) assay, for apoptosis by caspase 3 assay, for detoxification by proteasome 20S sub-unit activity and for skin hydration by aquaporin 3 (AQP3) membrane channels expression. Human subjects were tested to evaluate the effect of DSOC Serum, a topical formula for facial skin, on skin hydration by a corneometer. Results: UVB irradiation induced cell apoptosis in the epidermis of skin organ cultures and decreased their proteasome activity and AQP3 expression. Topical application of DSOC significantly attenuated all these effects. In human subjects, an elevation in the intense skin moisture, which was higher relatively to subjects’ regular moisturizer, was observed. Moreover, DSOC Serum boosted the hydration effect together with regular moisturizer. Conclusions: The results clearly demonstrate that DSOC preparation can significantly improve the skin capability in coping with UVB rays stress in different cellular functions such as anti-apoptotic properties as well as detoxification and hydration recovery that can attenuate biological effects of skin photo-damage. Topical application of DSOC Serum had contributed to skin appearance by a strong hydration impact, also as a booster.