Background Hepatocellular carcinoma (HCC) is a type of cancer that affects the liver and has a high mortality rate. Long non-coding RNAs (lncRNAs) dysregulation can contribute to cancer occurrence and progression, although the underlying molecular pathways are mostly unclear. HOXC-AS3 was found to be considerably overexpressed in HCC in this investigation. The goal of this work was to look into the involvement of HOXC-AS3 in HCC and the various molecular pathways that underpin it. Methods Normal liver and paired HCC tissues from HCC patients were used to evaluate HOXC-AS3 expression by qRT-PCR. The role of HOXC-AS3 in HCC was assessed both in vitro and in vivo. RNA pulldown, RIP and co-IP were used to demonstrate the potential mechanism by which HOXC-AS3 regulates the progression of HCC. Results Using qRT-PCR, it was discovered that HOXC-AS3 was substantially expressed in HCC. In vitro and in vivo, overexpression of HOXC-AS3 aided proliferation and cell cycle progression. HOXC-AS3 interacted with CDK2 to facilitate CDK2's decreased binding to p21, resulting in enhanced CDK2 activity, which promoted the phosphorylation of Rb and the progression of HCC. Conclusions HOXC-AS3 is highly expressed in HCC and can promote the progression of HCC by interacting with CDK2. Therefore, targeting HOXC-AS3 is very likely to provide a new strategy for the treatment of HCC and for improving patient prognosis.