Glucose-regulated protein 78 kDa (GRP78), a key marker of endoplasmic reticulum stress (ERS), is upregulated in hepatocellular carcinoma (HCC) tissues, but its role in hepatitis B virus (HBV)-induced tumorigenesis remains unclear. This study aimed to investigate the contribution of GRP78 to HBV-associated tumor development and explore the ERS pathways involved. The results showed that increased GRP78 expression in patients with HBV-related HCC was associated with a poor prognosis within the first 2 years following diagnosis. Furthermore, using wild-type HBV strain and the oncogenic HBV rtA181T/sW172* mutant, this study demonstrated that the HBV-induced GRP78 expression correlated with elevated reactive oxygen species (ROS) levels. Moreover, GRP78 expression enhanced hepatocyte proliferation and resistance to apoptosis. In wild-type HBV-infected hepatocytes, GRP78 suppressed apoptosis by inhibiting the PERK/p38 pathway. In contrast, the HBV rtA181T/sW172* mutation led to increased GRP78 expression and inhibition of cell apoptosis through activation of the IRE-1 alpha/XBP1/BCL-2 pathway. In conclusion, GRP78 plays a pivotal role in HBV-induced hepatocarcinogenesis by modulating distinct ERS pathways. Targeting these pathways may aid in the therapeutic management of HBV-associated hepatocarcinogenesis.