Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, have antioxidative potential, but the molecular mechanism of AA against oxidative stress remains unclear. Our study was performed to investigate the antioxidative effect of AA against oxidative stress and the antioxidative mechanism in tert-butyl hydroperoxide (t-BHP) -stimulated the HepG2 cells. The results showed that AA suppressed t-BHP-induced cytotoxicity, apoptosis, and reactive oxygen species (ROS) generation. Additionally, AA activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signal, which was closely related to induction Nrf2 nuclear translocation, reduction the expression of Keap1 and up-regulation the activity of the antioxidant response element (ARE). Meanwhile, activation of Nrf2 signal upregulated the protein expressions of antioxidant genes, including heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidase (NQO-1), and glutamyl cysteine ligase catalytic subunit (GCLC). Excitingly, Knockout of Nrf2 almost abolished AA-mediated antioxidant activity and cytoprotection against t-BHP. Further studies showed the mechanism underlying that AA induced Nrf2 activation in HepG2 cells via Akt and ERK signal activation. We found Akt and ERK inhibitors treatment attenuated AA-mediated Nrf2 nuclear translocation. Furthermore, treatment with either Akt or ERK inhibitor also decreased AA-mediated cytoprotection against t-BHP-induced cellular damage. Collectively, these results presented in this study indicate that AA has the protective effect against t-BHP-induced cellular damage and oxidative stress by modulating Nrf2 signaling through activating the signals of Akt and ERK.