Immunotherapy for hepatocellular carcinoma (HCC) often does not achieve the desired results. Immunogenic cell death (ICD) has significant potential to trigger the body’s immune response against tumors, offering a hopeful strategy to improve immunotherapy for HCC. Arsenic trioxide (ATO), which induces ICD, may markedly increase the effectiveness of programmed cell death protein 1 (PD-1) inhibitors in the therapy of HCC. However, the complex mechanisms behind this synergistic effect are not yet fully understood. This study aims to elucidate the functions and mechanisms of ATO in HCC and to explore its potential to enhance immunotherapy for HCC. The results showed that ATO dose-dependently reduced the viability of HCC cells. Concurrently, ATO treatment led to an increase in ROS levels and induced ERS, which activated ICD-related damage associated molecular patterns (DAMPs). As a result, this process prompted dendritic cell maturation and enhanced the tumor immune microenvironment. ATO treatment increased the immunogenicity of HCC cells, allowing them to function as both prophylactic and therapeutic vaccines against HCC and to augment anti-tumor immunity. Finally, ATO was found to improve the effectiveness of PD-1 inhibitors in treating HCC in vivo. Therefore, we conclude that ATO effectively bolstered the body’s immune response by triggering ROS/ERS-mediated ICD, which significantly enhanced the therapeutic effectiveness of PD-1 inhibitors against HCC.