Objective To investigate the clinical efficacy and safety of nivolumab （PD-1 inhibitor） in combination with lenvatinib and FOLFOX regimen ［5-fluorouracil （5-FU）， oxaliplatin （L-OHP）， and calcium folinate （LV）］ in the treatment of intermediate and advanced hepatocellular carcinoma （HCC） via hepatic arterial infusion chemotherapy （HAIC）. Methods A total of 160 patients with intermediate and advanced HCC admitted to the Second Affiliated Hospital of Guilin Medical University from January 2021 to January 2023 were randomly divided into the control group and the observation group， with 80 patients in each group， using a random number table. The control group received once-daily oral lenvatinib and intravenous carrizumab infusions for 12 weeks as part of transcatheter arterial chemoembolization （TACE） therapy. The observation group was administered with FOLFOX regimen via HAIC chemotherapy， plus intravenous infusion of carrizumab for 12 weeks and once-daily oral lenvatinib. All the patients were followed up regularly. The clinical efficacy was evaluated using the mRECIST criteria. The objective response rate （ORR）， disease control rate （DCR）， overall survival （OS）， progression-free survival （PFS）， and incidence of adverse reactions were compared between the two groups. Results There were no significant differences in the objective response rate and incidence of adverse reactions between the groups. The disease control rate， overall survival， and progression-free survival in the observation group were significantly higher than those in the control group （P < 0.05）. Conclusions The FOLFOX-HAIC regimen in combination with nivolumab and lenvatinib is safe and effective for the treatment of intermediate and advanced HCC， without adverse reactions. It can prolong the overall survival and progression-free survival， and improve the patient′s quality of life.