The retinoic acid-induced protein I (Rig-I/Ddx58), (RIG-I) initiates a signaling cascade that induces innate immune defences which is associated with the production of type I interferons (IFNs) and inflammatory cytokines to establish an antiviral state. Aberrant RIG-I signaling leads to inflammation, autoimmune diseases and cancer. However, the role of RIG-I in hepatocellular carcinoma (HCC) is still unknown. Here, we observed that RIG-I expression was downregulated in HCC tissues and loss of RIG-I expression was correlated with poor clinicopathological features. Additionally, we demonstrated that patients with positive RIG-I expression had a better 3-year survival and RIG-I was an independent factor for predicting the prognosis of HCC patients. Elevated RIG-I expression inhibited the proliferation, migration, and invasion of HCC. Inhibiting RIG-I with its specific siRNA was able to attenuate the malignant behavior of HCC cells. Moreover, RIG-I inhibited the invasive behavior through downregulating matrix metalloproteinase-9 (MMP9). Mechanistically, RIG-I enhances IFN-α response by amplifying IFN-α effecter signaling via strengthening STAT1 activation. Addressing this pathway, we identified that RIG-I may serve as a prognostic marker and that MMP9 may be a potential target of RIG-I in HCC.