Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality worldwide, which is characterized by aggressive growth and metastasis. However, the relationship between TOP2A and CDC6 and HCC remains unclear. GSE121248 and GSE101728 profiles for liver cancer were downloaded from the gene expression omnibus database generated using GPL21047and GPL570. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and survival analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to the core gene. TargetScan was used to screen miRNAs regulating central DEGs. 885 DEGs were identified. According to gene ontology analysis, they were mainly enriched in organic acid metabolism process, metabolic pathway, p53 signal pathway and PPAR signal pathway. The enrichment items are similar to the GOKEGG enrichment items of differentially expressed genes, mainly in the process of organic acid metabolism, p53 signal pathway and PPAR signal pathway. In the enrichment project of metascape, gene ontology has PIDPLK1 pathway, mitotic cell cycle, tumor retinoblastoma gene. The construction and analysis of protein-protein interaction network obtained 10 core genes (TOP2A, CDK1, ASPM, RACGAP1, ZWINT, CDC6, AURKA, NCAPG, BUB1B, CCNB1), and found that these core genes were highly expressed in tumor tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that 10 genes (TOP2A, CDK1, ASPM, RACGAP1, ZWINT, CDC6, AURKA, NCAPG, BUB1B, CCNB1) were related to necrosis, inflammation, HCC, liver cirrhosis, and adenoid cystic carcinoma. TOP2A and CDC6 are highly expressed in liver cancer, which may become molecular targets for early diagnosis and precise treatment.