Several studies have highlighted that Mago-nashi homolog (MAGOH) contributed greatly to cell development, growth, and malignant progression in multiple cancer types. Nevertheless, the role of MAGOH in pan-cancer datasets, particularly in hepatocellular carcinoma (HCC), remains uninvestigated. In this study, we first utilized diverse databases to systematically analyze the expression and significance of MAGOH across pan-cancer. Besides, we validated the clinical significance and biological functions of MAGOH in HCC via clinical specimens and in vitro experiments. Bioinformatic analysis has demonstrated that MAGOH was frequently overexpressed in multiple tumors compared to adjacent non-cancerous tissues. Moreover, high expression of MAGOH was related to poorer overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) in certain malignancies, notably an independent prognostic predictor for liver hepatocellular carcinoma (LIHC). Furthermore, MAGOH was closely correlated with immune cell infiltration, immune checkpoint expression, tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) status. Subsequently, we found that the expression of MAGOH was largely increased in clinical HCC tissues (34/60, 56.7%) compared to non-cancerous tissues. Additionally, MAGOH was positively correlated with advanced TNM staging and vascular invasion. More convincingly, MAGOH upregulation facilitated cell proliferation, migration, and invasion of HCC cells, while MAGOH depletion elicited opposite effects. Collectively, our study conducted a comprehensive analysis of the hitherto undescribed role of MAGOH in pan-cancer by analyzing multi-omics data. More significantly, we recognized MAGOH as a crucial promoter in the malignant progression of hepatocellular carcinoma, providing potential therapeutic targets for HCC patients.