Objective To explore the perioperative safety and prognostic factors of sequential hepatectomy after conversion therapy using vascular interventional therapy (including transarterial chemoembolization and hepatic arterial infusion chemotherapy) combined with tyrosine kinase inhibitors (TKI) and programmed death-1 (PD-1) inhibitors in patients with initially unresectable hepatocellular carcinoma. Methods The clinical data of 106 eligible HCC patients treated in Tumor Hospital Affiliated to Guangxi Medical University from Nov. 2019 to Apr. 2024 were retrospectively analyzed. The perioperative parameters and postoperative pathological outcomes were described in detail, and factors influencing prognosis were analyzed. Results The median operative time for hepatectomy after conversion therapy was 240 min, with a median blood loss of 200 mL. Intraoperative blood transfusion was required in 24 (22.6%) patients. Postoperative adverse reactions occurred in 49.1% (52/106) of patients, with liver failure being the most common adverse reactions (23 patients, 21.7%). One (0.9%) patient died during the perioperative period, while the remaining 105 patients were followed up for a median duration of 14.7 months, during which 49 (46.2%) patients experienced recurrence. Among them, 39 (36.8%) cases experienced early recurrence (within 1 year), and 33 (31.1%) cases had intrahepatic recurrence. Thirteen (12.3%) patients died during follow-up. The median recurrence-free survival (RFS) was 15.7 months, with 1-year and 2-year RFS rates being 56.9% and 40.3%, respectively. The median overall survival (OS) was not reached, with 1-year and 2-year OS rates being 94.2% and 85.3%, respectively. Multivariate Cox regression analysis demonstrated that achieving complete pathological response (hazard ratio ［HR］ ＝0.410, 95% confidence interval ［CI］ 0.172-0.980, P＝0.045), presence of microvascular invasion (HR＝2.423, 95% CI 1.269-4.625, P＝0.007), satellite nodules (HR＝1.916, 95% CI 1.014-3.620, P＝0.045), and multiple tumors (HR＝1.818, 95% CI 1.012-3.241, P＝0.046) were independent factors associated with postoperative recurrence. Conclusion For patients with initially unresectable hepatocellular carcinoma, vascular interventional therapy combined with TKI and PD-1 inhibitors followed by sequential hepatectomy may be a feasible treatment strategy, with manageable adverse reactions and promising efficacy.