The skin is constantly subject to external stressors (the exposome), including particulate matter and blue light. These can penetrate the deeper layers of the skin, inducing the release of free radicals and triggering an inflammatory cascade of events contributing to cutaneous aging and exacerbating inflammatory skin conditions. This study demonstrates the clinical efficacy of Indian sandalwood oil of varying concentrations against oxidative stress induced by urban dust and blue light. Twenty-two healthy human subjects entered and completed the study of 11 days. Test products containing 0.1%, 1% and 10% of sandalwood oil, as well as a placebo and a comparator control (α-tocopherol), were applied on the different investigational zones of the upper back of each subject. Exposure ensued on day 7, using a controlled pollution exposure system (CPES) and blue light at a wavelength of 412 nm. Sebum was sampled on each investigational zone following the last exposure. The level of squalene monohydroperoxide (SQOOH) was the primary endpoint. A dose-dependent decrease in SQOOH on the zones treated with 10%, 1% and 0.1% of the sandalwood oil formulation compared to the untreated zones was observed. The zone treated with the 10% sandalwood-containing formula demonstrated the highest protective efficacy with the lowest amount of SQOOH. Increasing the concentration of the sandalwood oil increased its protective antioxidant activity. The results collected from this intraindividual comparative is the first clinical trial to suggest that sandalwood oil at a concentration between 1% and 10% protects the skin against the oxidative stress induced by urban dust and blue light exposure.