Paclitaxel (PTX) is an effective chemotherapeutic agent for cancer patients. It has been reported that circular RNA (circRNA) circ_0005785is involved in the progression of hepatocellular carcinoma (HCC). The purpose of this study is to explore the role and mechanism of circ_0005785 in the PTX resistance of HCC. Cell viability, proliferation, invasion, migration, apoptosis, and angiogenesis were detected using 3‐(4, 5‐dimethyl‐2‐thiazolyl)‐2, 5‐diphenyl‐2‐H‐tetrazolium bromide (MTT), colony formation, transwell, wound‐healing, flow cytometry, and tube formation assay. Circ_0005785, microRNA‐640 (miR‐640), and Glycogen synthase kinase‐3 beta (GSK3β) levels were detected using real‐time quantitative polymerase chain reaction. Protein levels of Proliferating cell nuclear antigen (PCNA), Bcl‐2, and GSK3β were measured using western blot assay. After being predicted using Circular RNA interactome or TargetScan, binding between miR‐640 and circ_0005785 or GSK3β was verified using dual‐luciferase reporter and RNA Immunoprecipitation assay. PTX treatment could repress HCC cell viability, decrease circ_0005785 and GSK3β expression, and increase the miR‐640 level in HCC cell lines. Furthermore, circ_0005785 and GSK3β were increased, and miR‐640 was decreased in HCC tissues and cell lines. Moreover, circ_0005785 knockdown hindered proliferation, migration, invasion, angiogenesis, and boosted apoptosis in PTX‐treated HCC cells in vitro. In addition, circ_0005785 silencing improved the PTX sensitivity of HCC in vivo. Mechanistically, circ_0005785 acted as a sponge of miR‐640 to regulate GSK3β expression. PTX restrained HCC tumorigenesis partly via regulating the circ_0005785/miR‐640/GSK3β axis, hinting at a promising therapeutic target for the HCC treatment. [ABSTRACT FROM AUTHOR]