Introduction: Hepatocellular carcinoma (HCC) seriously endangers the life and health of people all over the world, so it is necessary to further study the pathogenesis of hepatocellular carcinoma. Kinesin family member 4A (KIF4A) appears to play oncogenic roles in numerous malignancies; however, its involvement in hepatocellular carcinoma (HCC) remains unclear. Methods: This study aimed to elucidate the molecular mechanisms underlying the biological function of KIF4A in HCC progression. Transcriptome sequencing was used to analyze changes in KIF4A expression during tumor progression. The functional roles of KIF4A in HCC cells were assessed through proliferation, migration, invasion, and metastasis assays conducted both in vitro and in vivo. Downstream molecules were identified using the 4D-DIA quantitative proteomics technique and bioinformatics analysis. Transcriptome sequencing confirmed up-regulated expression of KIF4A in HCC tissues, which increased with clinical progression. Additionally, in vivo experiments using subcutaneous xenograft tumor and xenograft mouse metastatic models confirmed that KIF4A facilitates HCC growth and metastasis. Results: Our study provides new insights into the clinical relevance and biological function of KIF4A in HCC. We found that KIF4A was significantly elevated in liver cancer tissues and was associated with poor prognosis in patients. Mechanistically, our results suggest that KIF4A promotes the proliferation and metastasis of HCC cells by inhibiting the degradation of HSP90 proteasome pathway, increasing the expression of the latter in HCC, and regulating AKT phosphorylation at Ser473 and Thr308 via the HSP90-CDC37 complex. These findings provide a novel theoretical foundation for understanding the molecular mechanisms of HCC progression, as well as presents novel targets developing treatments of HCC. Discussion: Our findings revealed up-regulated KIF4A expression in HCC cell lines and tissues, associated with poor prognoses for HCC patients. Overexpression of KIF4A promotes HCC cell progression. HSP90 emerges as a novel regulator of KIF4A, and KIF4A mediates HCC progression by regulating the HSP90-CDC37 complex /AKT pathway.