Malignant hepatoma is the leading cause of morbidity and mortality in primary liver cancer. MicroRNAs are widely accepted to act as tumor regulators to mediate tumorigenesis. Recently, miRNA-451 (miR-451) has attracted increasing attention due to its critical roles in the development of several types of cancers. Unfortunately, its function and underlying mechanism(s) of action in hepatoma remain unclear. In this study, a significant downregulation of miR-451 was observed in hepatoma cell lines. Its overexpression by administration of miR-451 mimics decreased cell viability and promoted cell apoptosis, indicating a critical role of miR-451 in cell growth. Further mechanistic analysis suggested that miR-451 overexpression accelerated cell death in a caspase-3-dependent manner, as pretreatment with its inhibitor z-VAD-fmk notably attenuated miR-451-induced cell apoptotic rates. Moreover, miR-451 upregulation abrogated cell invasive ability, accompanied with the decrease of matrix metalloproteinase-9 (MMP-9) expression levels, which may contribute to miR-451-triggered cell apoptosis. Taken together, these results reveal a prominent role of miR-451 as a tumor suppressor regulating hepatoma cell growth and invasion in a caspase-3- and MMP-9-dependent manner. Thus, our research supports this promising therapeutic agent against hepatoma.