Anaplastic thyroid cancer (ATC) is a rare type of thyroid cancer with a high mortality rate. HLA complex P5 (HCP5), a long non-coding RNA (lncRNA), has been shown to be implicated in several types of cancer, such as follicular thyroid carcinoma (PTC), the main type of thyroid cancer. However, the role of HCP5 in ATC remains unclear. The present study aimed to investigate the expression of HCP5 in ATC and its potential roles. The expression levels of HCP5 and microRNA (miR)-128-3p were tested using qRT-PCR. MTT assay was performed to detect cell viability. Cell apoptosis was evaluated by detecting apoptotic rate and caspase-3/7 activity. Luciferase reporter and RNA immunoprecipitation (RIP) assays were carried out to confirm the association between HCP5 and miR-128-3p. Compared with human thyroid follicular cell line Nthy-ori 3-1 cells, HCP5 expression level was significantly increased in ATC cell lines. Besides, HCP5 expression level was increased in ATC tissues when compared with adjacent normal tissues. Knockdown of HCP5 reduced cell viability, while elevated apoptotic rate and caspase-3/7 activity in ARO and SW1736 cells. MiR-128-3p was predicted to be a target gene of HCP5. The expression level of miR-128-3p was significantly decreased in ATC cells and tissues, as compared to Nthy-ori 3-1 cells and adjacent normal tissues, respectively. MiR-128-3p overexpression reduced ATC cell viability, and induced cell apoptosis. HCP5 directly bound to miR-128-3p and regulated the expression of miR-128-3p in ARO and SW1736 cells. Furthermore, the effects of HCP5 knockdown on ATC cell viability and apoptosis were attenuated by the inhibitor of miR-128-3p. These findings suggested that knockdown of HCP5 exerted anti-tumor effect via sponging miR-128-3p in ATC, which might provide a potential approach for the treatment of ATC.