This study was to investigate the potential mechanism of triptolide-induced hepatotoxicity. We found a novel and variable role of p53/Nrf2 crosstalk in triptolide-induced hepatotoxic process. Low doses of triptolide led to adaptive stress response without obvious toxicity, while high levels of triptolide caused severe adversity. Correspondingly, at the lower levels of triptolide treatment, nuclear translocation of Nrf2 as well as its downstream efflux transporters multidrug resistance proteins and bile salt export pump expressions were significantly enhanced, so did p53 pathways that also increased; at a toxic concentration, total and nuclear accumulations of Nrf2 decreased, while p53 showed an obvious nuclear translocation. Further studies showed the cross-regulation between p53 and Nrf2 after different concentrations of triptolide treatment. Under mild stress conditions, Nrf2 induced p53 highly expression to maintain the pro-survival outcome, while p53 showed no obvious effect on Nrf2 expression and transcriptional activity. Under high stress conditions, the remaining Nrf2 as well as the largely induced p53 mutually inhibited each other, leading to a hepatotoxic result. Nrf2 and p53 could physically and dynamically interact. Low levels of triptolide enhanced the interaction between Nrf2 and p53. Reversely, p53/Nrf2 complex dissociated at high levels of triptolide treatment. Altogether, variable p53/Nrf2 crosstalk contributes to triptolide-induced self-protection and hepatotoxicity, modulation of which may be a potential strategy for triptolide-induced hepatotoxicity intervention.