OBJECTIVE: Oxidative stress activates the reactive oxygen species (ROS) and excessive ROS can damage skin cells, initiating oxidative stress responses that contribute to inflammation, aging, and other skin issues. As a resident skin bacterium, Cutibacterium acnes (C. acnes) plays an important role in maintaining skin homeostasis and provides antioxidant benefits. However, the metabolite components and mechanisms of C. acnes exerting antioxidant activity are not yet clear. This study aimed to analyze the potential antioxidant effects of C. acnes cell-free supernatant and the mechanisms. METHODS: The antioxidant effects were evaluated by measuring the scavenging activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid ammonium salt) (ABTS) radicals, and hydroxyl radicals, as well as the effects on ROS levels in menadione-induced primary human keratinocytes in vitro. Additionally, western blot analysis was performed to assess the antioxidant effects of the C. acnes CCSM0331 cell-free supernatant (CFS). RESULTS: C. acnes CCSM0331 was isolated from the facial skin of healthy individuals. This strain, classified as type II, is associated with healthy skin. The CFS of strain CCSM0331 contained various short-chain fatty acids (SCFAs), glutathione peroxidase (GSH-Px), and total superoxide dismutase(T-SOD), exhibiting strong DPPH and ABTS radical scavenging capabilities, thus demonstrating substantial antioxidant activity. In a reactive oxygen species model induced by menadione in primary human keratinocytes, the addition of 5% of the fermentation supernatant from this strain significantly reduced ROS levels, indicating a notable ROS-scavenging effect. Western blot analysis further confirmed that the CCSM0331 fermentation supernatant activated the expression of Nrf-2 and HO-1 proteins, thereby activating the Nrf-2 oxidative stress pathway and exerting antioxidant effects. CONCLUSION: C. acnes CCSM0331 is a promising skin probiotic with notable antioxidant properties. The activity of this strain exhibited significant free radical scavenging activity, suggesting its potential application in the development of antiaging products. This study provides theoretical support for the screening of functional skin bacteria or skin probiotics.