Long non‑coding RNAs (lncRNAs) have recently gained attention due to their important roles in human cancer types, such as breast and gastric cancer. The present study measured alterations in muskelin 1 antisense RNA (MKLN1‑AS) expression in hepatocellular carcinoma (HCC) and evaluated its clinical value in patients with HCC. Additionally, the current study investigated the effects of MKLN1‑AS on the malignant features of HCC cells. The detailed molecular mechanisms underlying the cancer‑promoting activities of MKLN1‑AS in HCC cells were also elucidated. MKLN1‑AS expression in HCC tissues and cell lines was detected using reverse‑transcription quantitative PCR (RT‑qPCR). Cell Counting Kit‑8 assays and flow cytometry were used to determine the roles of MKLN1‑AS in HCC cell proliferation and apoptosis. Migration and invasion assays, as well as tumor xenograft experiments were conducted to analyze migration and invasion in vitro and tumor growth in vivo, respectively. The interaction among microRNA‑654‑3p (miR‑654‑3p), MKLN1‑AS and hepatoma‑derived growth factor (HDGF) in HCC was investigated using luciferase reporter assay, RNA immunoprecipitation assay, RT‑qPCR, western blotting and rescue experiments. MKLN1‑AS was upregulated in HCC tissues and cell lines, and a high MKLN1‑AS expression was associated with shorter overall survival and disease‑free survival in patients with HCC. Functionally, the knockdown of MKLN1‑AS impaired HCC cell proliferation, migration and invasion, as well as induced cell apoptosis in vitro. Knockdown of MKLN1‑AS expression also inhibited cell proliferation in vivo. The results indicated that MKLN1‑AS functioned as a competing endogenous RNA by sponging miR‑654‑3p in HCC cells. Additionally, miR‑654‑3p targeting of HDGF was positively modulated by MKLN1‑AS, and miR‑654‑3p knockdown partially abrogated this effect. Rescue experiments demonstrated that knockdown of miR‑654‑3p and overexpression of HDGF both abolished MKLN1‑AS knockdown‑induced cellular processes in HCC. In summary, MKLN1‑AS induced pro‑oncogenic effects during HCC progression by serving as a molecular sponge for miR‑654‑3p to increase HDGF expression. Therefore, the MKLN1‑AS/miR‑654‑3p/HDGF axis may offer a novel target for the diagnosis, prognosis, prevention and treatment of HCC.