Since the skin is one of the targets of the harmful effects of environmental insults, several studies have investigated the effects of outdoor stressors on cutaneous tissue. Ozone (O), particulate matter (PM), and ultraviolet radiation (UV) have all been shown to induce skin damage through disruption of tissue redox homeostasis, resulting in the so called "OxInflammation" condition. However, few studies have explored whether these stressors can act synergistically in cutaneous tissues. In the present work, we evaluated whether O, PM, and UV, which are the most common environmental skin insults, act synergistically in inducing skin damage, and whether this effect could be prevented through topical application of a cosmeceutical formulation mixture (CF Mix) containing 15% vitamin C (l-ascorbic acid), 1% vitamin E (α-tocopherol), and 0.5% ferulic acid. Human skin explants obtained from three different subjects were sequentially exposed to 200 mJ UV light, 0.25 ppm O for 2 h, and 30 min of diesel engine exhaust (DEE), alone or in combination for 4 days (time point D1 and D4). We observed a clear additive effect of O and DEE in combination with UV in increasing levels of several oxidative (4HNE, HO-1) and inflammatory (COX2, NF-κB) markers and loss of barrier-associated proteins, such as filaggrin and involucrin. Furthermore, daily topical pre-treatment with the CF Mix prevented upregulation of the inflammatory and oxidative markers and the loss of both involucrin and filaggrin. In conclusion, this study is the first to investigate the combined effects of three of the most harmful outdoor stressors on human skin and suggests that daily topical application may prevent pollution-induced skin damage.