Background: Emerging evidence suggests that circular RNAs (circRNAs) play critical roles in tumorigenesis. However, the roles and molecular mechanism of circRNA leucine-rich repeat immunoglobulin domain-containing protein 3 (circ_LRIG3) in hepatocellular carcinoma (HCC) have not been investigated.Methods: The expression levels of circ_LRIG3, microRNA-223-3p (miR-223-3p), and mitogen-activated protein kinase kinase 6 (MAP2K6) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Flow cytometry was applied to determine the cell cycle distribution and cell apoptosis. Cell proliferation, migration and invasion were assessed by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and transwell assay, respectively. Western blot assay was employed to measure the protein levels of snail, E-cadherin, MAP2K6, mitogen-activated protein kinase (MAPK), phospho-MAPK (p-MAPK), extracellular signal-regulated kinases (ERKs), and phospho-ERKs (p-ERKs). The relationship between miR-223-3p and circ_LRIG3 or MAP2K6 was predicted by bioinformatics tools and verified by dual-luciferase reporter assay. A xenograft tumor model was established to confirm the functions of circ_LRIG3 in vivo.Results: Circ_LRIG3 and MAP2K6 expression were enhanced while miR-223-3p abundance was reduced in HCC tissues and cells. Knockdown of circ_LRIG3 inhibited the progression of HCC cells via reducing cell proliferation, metastasis and increasing apoptosis. MiR-223-3p was a target of circ_LRIG3 and its downregulation reversed the inhibitory effect of circ_LRIG3 knockdown on progression of HCC cells. Moreover, MAP2K6 could bind to miR-223-3p, and MAP2K6 upregulation also abolished the suppressive impact of circ_LRIG3 interference on progression of HCC cells. Additionally, silence of circ_LRIG3 suppressed the activation of MAPK/ERK pathway and tumor growth by upregulating miR-223-3p and downregulating MAP2K6.Conclusion: Circ_LRIG3 knockdown inhibited HCC progression through regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway, providing a potential therapeutic approach for patients with HCC.