Background The most part of primary liver cancer is hepatocellular carcinoma having a poor prognosis. The treatment strategies including multitarget inhibitors, ICIs, and new options are being explored. Recently studies demonstrated the synergistic effect of anti-angiogenesis-targeted drugs combined with immunotherapy. In this study, we explored toripalimab combined with anlotinib as second-line therapy to evaluate the safety and efficacy in advanced hepatocellular carcinoma (HCC). Patients and methods: Twenty-six patients diagnosed with HCC and experienced disease progression or drug intolerance after first-line targeted therapy were included in this study. All enrolled patients received toripalimab combined with anlotinib. The primary endpoint of this study was the objective response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and disease control rates (DCR). Results Finally 22 patients met the protocol were included in the data analysis. The ORR was 7.69%, the mPFS was 3.12 months, mOS was 10.89 months, and DCR was 42.31%, among which 1 patient achieved CR, 1 patient achieved PR, and 9 patients achieved SD. By the last follow-up, the duration of CR in patients had been more than 2 years. No treatment-related deaths occurred, generally this combination therapy is well tolerated. Conclusion In patients who experience disease progression with first-line sorafenib or lenvatinib, toripalimab combined with anlotinib may be a good choice for second-line treatment and is well tolerated. TP53 mutations may serve as biomarkers for this treatment and larger sample size is required for further confirmation.