Celecoxib inhibits β-catenin-dependent survival of the human osteosarcoma MG-63 cell line. Cyclo-oxygenase (COX)-2 inhibitors may exert antitumour effects through COX-2-independent mechanisms. This study investigated the effects of the COX-2 inhibitor celecoxib on the viability of the human osteosarcoma MG-63 cell line and its β-catenin signalling pathway. Cell viability and apoptosis were examined in celecoxib-treated cells or after β-catenin knockdown in vitro. Analyses were performed to detect glycogen synthase kinase (GSK)-3β, phosphorylated GSK-3β, β-catenin, c-Myc and cyclin D1 proteins, and mRNA levels of β-catenin, c-Myc and CCND1 (encoding cyclin D1). β-Catenin was shown to be required for MG63 cell survival and celecoxib exerted an inhibitory effect on the viability of cultured MG-63 cells in a time- and dose-dependent manner. β-Catenin protein decreased in the cytosol and nucleus following celecoxib treatment (from 6 h after initiation of treatment onwards; lowest protein levels were reached at > 72 h). Significant reductions in β-catenin, c-Myc and CCND1 mRNA were observed. Celecoxib inhibited MG-63 cell viability, possibly by activating GSK-3β and inhibiting β-catenin-dependent gene transcription, suggesting a role for celecoxib in osteosarcoma treatment.