The polyphenol content of fresh and dried Litsea cubeba fruits was analyzed using the Folin-ciocalteu method, whereas their in vitro antioxidant activity was evaluated using the oxygen radical absorbance capacity (ORAC) and peroxyl radical scavenging capacity (PSC) assays. Additionally, an oxidative stress model was established using H2O2-induced HepG2 cells to explore the protective mechanism of L. cubeba fruit polyphenols against oxidative damage. The results indicated that the total polyphenol content of fresh fruits (2 053.29 mg GAE/100 g) was 4.99-fold higher than that of dried fruits (411.47 mg GAE/100 g), with approximately 90% existing in free form. The antioxidant activity of fresh fruit polyphenols was significantly stronger than that of dried fruits, with higher ORAC/PSC values. High mass concentrations of L. cubeba fruit polyphenols increased the viability of oxidatively damaged HepG2 cells by 2- to 3-fold, significantly enhanced superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels, and reduced lactate dehydrogenase (LDH) and reactive oxygen species (ROS) levels. At the molecular level, the polyphenols activated the Nrf2/NQO1 signaling pathway and upregulated gene expression of downstream antioxidant enzymes (SOD1, CAT, and GSS) to alleviate oxidative stress effects. These findings provide a theoretical foundation for the application of L. cubeba fruit polyphenols in functional foods.