Background: Angiogenesis plays an important role in the occurrence, development and metastasis of hepatocellular carcinoma (HCC). miR-378a-3p participates in tumorigenesis and tumor metastasis according to previous studies, yet the exact role it plays in HCC angiogenesis remains poorly understood.Methods: qRT-PCR was used to investigate the expression of miR-378a-3p in HCC tissues and cell lines. The effects of miR-378a-3p on HCC in vitro and in vivo were examined by CCK-8, transwell assay, tube formation and matrigel plug assay. RNA sequencing, bioinformatics analysis, luciferase reporter assay, immunofluorescence assay and ChIP assay were used to detected the molecular mechanism of miR-378a-3p-induced inhibition of angiogenesis. Results: We confirmed that the expression of miR-378a-3p was significantly downregulated and was associated with microvascular density (MVD) in HCC, which indicated a short survival time of HCC patients, and reducing miR-378a-3p expression led to a significant increase in angiogenesis in vitro and in vivo. miR-378a-3p directly targeted TNF receptor associated factor 1 (TRAF1) to attenuate NF-κB signaling, and then decreases secreted vascular endothelial growth factor (VEGF). DNA methyltransferase 1 (DNMT1) mediated hypermethylation of miR-378a-3p was responsible for downregulating of miR-378a-3p. Moreover, a series of investigation indicated that p65 initiated a positive feedback loop, which could up-regulate DNMT1 to promote hypermethylation of the miR-133a-3p promoter.Conclusion: Our study indicates that a novel DNMT1/miR-378a-3p/TRAF1/ NF-κB positive feedback loop in HCC cells, which may become a potential therapeutic target for HCC.