Liver cancer is one of the most prevalent and fatal malignancies, disproportionately affecting males. This gender disparity is influenced by estrogen, which acts through receptors like the G-protein-coupled estrogen receptor (GPER), known to regulate cell proliferation and migration. We examined the effects of GPER activation and inhibition in liver cancer cell lines using the agonist G1 and antagonist G15. G1 treatment significantly reduced cell viability and colony formation. Proteomics and RNA sequencing identified ADAMTS-1, a protein involved in inflammation and anti-angiogenesis, as being upregulated at both RNA and protein levels after G1 treatment. Western blot analysis confirmed increased ADAMTS-1 expression. In a liver cancer xenograft mouse model, G1 administration inhibited tumor growth, suggesting that GPER activation suppresses liver cancer cell proliferation. Our findings indicate that GPER-mediated upregulation of ADAMTS-1 may contribute to this suppression, with potential implications for inflammation regulation. Targeting ADAMTS-1 expression could serve as a novel therapeutic strategy for managing liver cancer progression.