The outcomes following anterior approach (AA) hepatectomy in huge hepatocellular carcinoma (HCC) patients with diaphragmatic invasion (DI) remain unclear. This study compared the outcomes of single huge right HCC patients with and without DI after AA hepatectomy. A total of 203 consecutive patients with single huge right lobe HCC who underwent AA major hepatectomy were included. They were divided into group PDI (n = 53) and group ADI (n = 150) according to the presence or the absence of DI. Their short- and long-term outcomes were compared, and a subgroup analysis was performed. There were no significant differences regarding postoperative complications and 90-day mortality between the 2 groups. The overall survival (OS) and recurrence-free survival (RFS) rates were similar between the 2 groups. The subgroup analysis also showed that patients with tumor resection en bloc with part of the diaphragm had similar OS and RFS rates as those who underwent diaphragmatic resection after hepatectomy. Tumor diameter ≥ 15 cm, serum AFP level ≥ 400 ng/mL, and tumor grade of G4 and microvascular invasion are independent predictors of poor prognosis. For the single huge right lobe HCC patients with DI, AA major hepatectomy combined with diaphragmatic resection could offer similar OS and RFS as those without diaphragmatic invasion.