Hepatoblastoma is the most common malignant liver tumor in children. Since it is often unresectable and exhibits drug resistance, the treatment of advanced hepatoblastoma is challenging. The orphan nuclear receptor liver receptor homolog‑1 (LRH‑1) serves prominent roles in malignancy; however, to the best of our knowledge, the role of LRH‑1 in hepatoblastoma remains unknown. In the present study, human hepatoblastoma cell lines were analyzed; the mRNA and protein expression levels of LRH‑1 were significantly higher in HepG2 and HuH6 cells compared with those in HepT1 cells and control THLE‑2 cells. Knockdown of LRH‑1 resulted in decreased HepG2 and HuH6 cell proliferation via downregulation of cyclin D1 (CCND1) and c‑Myc. Furthermore, treatment with an LRH‑1 antagonist (LRA) inhibited the proliferation and colony formation of cell lines in a dose‑dependent manner, and induced cell cycle arrest at G1 phase through inhibition of CCND1 expression. Finally, LRA treatment enhanced the cytotoxic effects of doxorubicin on hepatoblastoma cells. Collectively, these findings suggested that LRH‑1 may have an important role in the progression of hepatoblastoma and implicated LRA as a novel, potential therapeutic agent for the treatment of hepatoblastoma.