Free radicals are associated with aging and many diseases. Antioxidant peptides with good antioxidant activity and absorbability are one of the hotspots in antioxidant researches. In our study, pearl shell (Pinctada martensii) meat hydrolysate was purified, and after identification by proteomics, six novel antioxidant peptides SPSSS, SGTAV, TGVAS, GGSIT, NSVAA, and GGSLT were screened by bioinformatics analysis. The antioxidant peptides exhibited good cellular antioxidant activity (CAA) and the CAA of SGTAV (EC50: 0.009 mg/mL) and SPSSS (EC50: 0.027 mg/mL) were better than that of positive control GSH (EC50: 0.030 mg/mL). In the AAPH-induced oxidative damage models, the antioxidant peptides significantly increased the viability of HepG2 cells, and the cell viability of SGTAV, SPSSS, and NAVAA were significantly restored from 79.41% to 107.43% and from 101.09% and 100.09%, respectively. In terms of antioxidant mechanism by molecular docking, SGTAV, SPSSS, and NAVAA could tightly bind to free radicals (DPPH and ABTS), antioxidant enzymes (CAT and SOD), and antioxidant channel protein (Keap1), suggesting that the antioxidant peptides had multiple antioxidant activities and had structure-activity linkages. This study suggests that the antioxidant peptides above are expected to become new natural materials for functional food industries, which contribute to the high-value applications of pearl shell meat.