Most patients with advanced hepatocellular carcinoma (HCC) ultimately experience tumor progression after first-line systemic therapies. Systemic therapy is generally recommended as second-line treatment for advanced HCC in the major guidelines. Combining apatinib with hepatic arterial infusion chemotherapy (HAIC) likely drives synergistic activity on advanced HCC with extrahepatic metastasis. This phase II trial (ChiCTR2000029082) aimed to assess efficacy and safety of this combination in patients with HCC with extrahepatic metastasis who have progressed after first-line systemic therapies. The primary end point was the objective response rate (ORR). The secondary endpoints were progress-free survival (PFS), disease control rate (DCR), 6- and 12-month survival rates, overall survival (OS), and adverse events (AEs). Thirty-nine patients received oral treatment with apatinib, and hepatic artery infusion oxaliplatinplus raltitrexed. Per RECIST v1.1, the ORR and DCR was 53.8% and 89.7% in the patients population, respectively. The median PFS and OS was 6.2 months and 11.3 months, respectively. The 6- and 12-month survival rates were 81.7% and 44.1%, respectively. All AEs were manageable by medication or dose modifications. Apatinib plus HAIC for second-line therapy in advanced HCC with extrahepatic metastasis shows promising efficacy and manageable toxicities.