Background <p>Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm with high incidence and dismal prognostic outcomes.</p> Purpose <p>This study sought to validate the prognostic significance of miR-4725-3p in HCC and the possible molecular mechanism.</p> Methods <p>A total of 117 HCC patients were stratified into two groups according to the median expression level of miR-4725-3p. Following a 5-year follow-up with death as the end event, a Kaplan-Meier curve was drawn. The potential risk factors for poor prognosis were evaluated using Cox regression analysis. Cell Counting Kit-8 (CCK-8) and Transwell assay were employed to assess the role of miR-4725-3p silencing on Huh-7 and Hep3B cells viability and migration. Downstream target genes of miR-4725-3p were predicted, and a dual-luciferase assay was conducted to verify the interaction.</p> Results <p>MiR-4725-3p was significantly upregulated in HCC tissue and cell line. Survival analysis showed that high miR-4725-3p expression was associated with poor prognosis in HCC patients (log-rank <i>P</i> = 0.006). At the cellular level, silencing miR-4725-3p significantly suppressed the viability and migration of Huh-7 and Hep3B cells. Mechanistically, activating transcription factor 5 (ATF5) was identified as a direct target of miR-4725-3p. ATF5 was downregulated in HCC tissue and cells.</p> Conclusion <p>The results of this study revealed that miR-4725-3p serves as a promising prognostic biomarker for HCC, and its oncogenic role in promoting HCC cell viability and migration may be mediated, at least in part, via the negative regulation of ATF5.</p>