Currently, radiofrequency ablation (RFA) has been the most widely used treatment for hepatocellular carcinoma (HCC). However, accumulating evidence has demonstrated that insufficient RFA (IRFA) may result in rapid progression of residual HCC which can greatly hinder the effectiveness of this technique. Although many efforts have been proposed, the underlying mechanisms triggering the rapid progression of residual HCC after IRFA have not yet been fully clarified. It was shown in this study that cell proliferation, migration and invasion of residual HepG2 and SMMC7721 cells were significantly increased after the IRFA simulated in vitro. What’s more, IRFA could do this by enhancing autophagy of the residual HCC cell via the HIF-1α/BNIP3 pathway. Down-regulation of BNIP3 may result in the inhibition of the residual HCC cell progression and autophagy after IRFA. Our present results suggest that IRFA could promote residual HCC cell progression in vitro by enhancing autophagy via the HIF-1α/BNIP3 pathway. Targeting the BNIP3 may be useful in preventing the rapid growth and metastasis of residual HCC after IRFA.