| Summary: | In this study, the lactobacillus fermentation process of pomegranate (<i>Punica granatum</i> L.) peel and <i>Schisandra chinensis</i> (Turcz.) Baill (PP&SC) was optimized by using the response surface method (RSM) coupled with a Box-Behnken design. The optimum fermentation condition with the maximal yield of ellagic acid (99.49 ± 0.47 mg/g) was as follows: 1:1 (<i>w</i><i>:</i><i>w</i>) ratio of pomegranate peel to <i>Schisandra chinensis</i>, 1% (<i>v:v</i>) of strains with a 1:1 (<i>v:v</i>) ratio of <i>Lactobacillus Plantarum</i> to <i>Streptococcus Thermophilus</i>, a 37 °C fermentation temperature, 33 h of fermentation time, 1:20 (g:mL) of a solid–liquid ratio and 3 g/100 mL of a glucose dosage. Under these conditions, the achieved fermentation broth (FB) showed stronger free radical scavenging abilities than the water extract (WE) against the ABTS<sup>+</sup>, DPPH, OH<sup>−</sup> and O<sub>2</sub><sup>−</sup> radicals. The cytotoxicity and the protective effect of FB on the intracellular ROS level in HaCaT cells were further detected by the Cell Counting Kit-8 (CCK-8) assay. The results showed that FB had no significant cytotoxicity toward HaCaT cells when its content was no more than 8 mg/mL. The FB with a concentration of 8 mg/mL had a good protective effect against oxidative damage, which can effectively reduce the ROS level to 125.94% ± 13.46% (<i>p</i> < 0.001) compared with 294.49% ± 11.54% of the control group in H<sub>2</sub>O<sub>2</sub>-damaged HaCaT cells. The outstanding antioxidant ability and protective effect against H<sub>2</sub>O<sub>2</sub>-induced oxidative damage in HaCaT cells promote the potential for the FB of PP&SC as a functional raw material of cosmetics.
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