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Phenolics were extracted from grape peels, and the compounds of grape peel phenolics (GPP) were identified by LC-MS/MS. From a perspective of dietary nutrition, this study aimed to evaluate the effect of GPP on lipid accumulation in sodium palmitate (PA)-treated HepG2 cells, and further to explore its mechanisms. HepG2 cells were induced by 0.4 mmol/L PA as an in vitro model of lipid accumulation. The results showed that GPP could significantly reduce the TG level and ROS production in PA-treated HepG2 cells. RT-qPCR and Western blotting analysis indicated that GPP supplementation can downregulate the mRNA and protein expression of lipogenesis factors and upregulate the expression of lipolysis factors in PA-treated cells. GPP reduced lipid accumulation and oxidative stress by activating the AMPK/mTOR/AKT signaling pathways, and the most significant effect was detected at 250 μg/mL GPP. Thus, GPP as a dietary phenolic, have the function to regulate lipid metabolism.