The clinical application of cellular immunotherapy in hepatocellular carcinoma (HCC) is impeded by the lack of a cell surface target frequently expressed in HCC cells and with minimal presence in normal tissues to reduce on-target, off-tumor toxicity. To address this, an in silico multomics analysis was conducted to identify an optimal therapeutic target in HCC. A longlist of genes (n = 12,948) expressed in HCCs according to The Human Protein Atlas database were examined. Eight genes were shortlisted to identify one with the highest expression in HCCs, without being shed into circulation, and with restrictive expression profile in other normal human tissues. A total of eight genes were shortlisted and subsequently ranked according to the combination of their transcript and protein expression levels in HCC cases (n = 791) derived from four independent datasets. TM4SF4 was the top-ranked target with the highest expression in HCCs. TM4SF4 showed more favorable expression profile with significantly lower expression in normal human tissues but more highly expressed in HCC compared with seven other common HCC therapeutic targets. Furthermore, scRNA-seq and immunohistochemistry datasets showed that TM4SF4 was absent in immune cell populations but highly expressed in the bile duct canaliculi of hepatocytes, regions inaccessible to immune cells. In scRNA-seq dataset of HCCs, TM4SF4 expression was positively associated with mitochondrial components and oxidative phosphorylation Gene Ontologies in HCC cells (n = 15,787 cells), suggesting its potential roles in mitochondrial-mediated oncogenic effects in HCC. Taken together, TM4SF4 is proposed as a promising cell surface target in HCC due to its high expression in HCC cells with restricted expression profile in non-cancerous tissues, and association with HCC oncogenic pathways.