Oxidative stress plays a critical role in drug-induced liver injury. In recent years, liquiritigenin (LQ), a natural flavonoid distributed in Glycyrrhizae Radix et Rhizoma (Gan Cao), shows protective effects against oxidative hepatotoxicity. However, the underlying mechanism remains unclear. In this study, we mainly investigated the role of NRF2, a core transcription factor in oxidative stress, in LQ-induced hepatoprotection. Our results indicated that the function of LQ to eliminate reactive oxygen species in liver cells was dependent on NRF2 activation. Both a canonical signaling pathway and a non-canonical signaling pathway are involved in LQ-induced NRF2 activation. LQ induced NRF2 activation in a KEAP1-C151-dependent manner partially. Meanwhile, LQ led to the blockage of autophagic flux and upregulation of p62, which competitively bound with KEAP1 and conferred NRF2 activation in a KEAP1-C151-independent manner. Totally, our study reveals a novel molecular mechanism underlying the hepatoprotection of LQ, providing a new insight into the pathogenesis and therapeutic strategy of oxidative liver injury.