Hepatocellular carcinoma (HCC) is one of the most common malignancies with a rising incidence around the world. MicroRNAs (miRNAs) have been reported to play essential roles in the progression of HCC. However, the precise mechanism of miR-3662 in the HCC process remains poorly understood. This study was aimed to determine the regulatory network of miR-3662 and hexokinase 2 (HK2) in HCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect miR-3662 expression. Cell proliferation and invasion were measured by Cell Counting Kit-8 (CCK-8) assay and Transwell assay, respectively. Glucose consumption and lactate production assays were used to detect glucose metabolism activity in HCC cells. The potential binding sites between miR-3662 and HK2 were predicted by TargetScan online software and the relationship between miR-3662 and HK2 was verified by luciferase report assay. The protein expression of HK2 was measured by western blot analysis. A xenograft tumor model was established to confirm the role of miR-3662 and HK2 in vivo. miR-3662 expression was downregulated in HCC tissues and cells, and it was reduced in hypoxia-induced HCC cells in a time-dependent manner. Overexpression of miR-3662 or knockdown of HK2 inhibited cell proliferation, invasion, and glucose metabolism in HCC cells, which could be reversed by upregulating HK2. Besides, HK2 was a direct target of miR-3662 in HCC cells, and hypoxia upregulated the expression of HK2. In addition, the upregulation of HK2 could abolish miR-3662 overexpression-induced inhibitory effects on tumor growth and glucose metabolism in vivo.