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Abstract A variety of microRNAs (miRNAs) are involved in the occurrence and development of hepatocellular carcinoma (HCC). However, the role of miR‐10a‐5p in the progression of HCC remains unclear. Therefore, the purpose of this study was to determine the role of miR‐10a‐5p in the development of HCC and the possible molecular mechanism. miR‐10a‐5p expression in HCC tissues and plasma from patients was detected by quantitative real‐time polymerase chain reaction. Migratory changes in HCC cells were detected after the overexpression of miR‐10a‐5p. Epithelial–mesenchymal transition (EMT)‐related proteins were detected by Western blot. Finally, through luciferase assay and rescue experiments, the mechanism by which miR‐10a‐5p regulates its downstream gene, human spindle and kinetochore‐associated complex subunit 1, SKA1 and the interaction between these molecules in the development of HCC were determined. The expression of miR‐10a‐5p was markedly downregulated in HCC tissues, cell lines, and plasma. The overexpression of miR‐10a‐5p significantly inhibited the migration, invasion, and EMT of HCC cells. Furthermore, SKA1 was shown to be a downstream gene of miR‐10a‐5p. SKA1 silencing had the same effect as miR‐10a‐5p overexpression in HCC. In particular, the overexpression of SKA1 reversed the inhibitory effects of miR‐10a‐5p in HCC. Taken together, low miR‐10a‐5p expression is associated with HCC progression. miR‐10a‐5p inhibits the malignant development of HCC by negatively regulating SKA1.