oral squamous cell carcinoma (oScc) is a cancer associated with high mortality (accounting for 3.1/100,000 deaths per year in Brazil in 2013) and a high frequency of amplification in the expression of the epidermal growth factor receptor (EGFR). Treatment with the EGFR inhibitor cetuximab leads to drug resistance in patients with oScc due to unknown mechanisms. Galectin-3 (Gal-3) is a β-galactoside binding lectin that regulates multiple signaling pathways in cells. The present study aimed to investigate the effect of Gal-3 in cetuximab-resistant (cet-R) OSCC. The OSCC HSC3 cell line was selected to establish a mouse xenograft model, which was treated with cetuximab to induce resistance. Subsequently, a Gal-3 inhibitor was used to treat cet-r tumors, and the tumor volume was monitored. The expression of Gal-3, phosphorylated (p)-erK1/2 and p-akt was assessed using immunohistochemistry. The combined effect of cetuximab and the Gal-3 inhibitor on HSC3 tumor xenografts was also investigated. HSc3 cells were cultured in vitro to investigate the regulatory effects of Gal-3 on erK1/2 and akt via western blotting. in addition, the effects of the Gal-3 inhibitor on the proliferation, colony formation, invasion and apoptosis of HSc3 cells were investigated by performing cell counting Kit-8, colony formation, Transwell and apoptosis assays, respectively. In cet-R OSCC tumors, increased expression of Gal-3, p-erK1/2 and p-akt was observed. Further research demonstrated that Gal-3 regulated the expression of both erK1/2 and akt in HSc3 cells by promoting phosphorylation. Moreover, the Gal-3 inhibitor decreased the proliferation and invasion, but increased the apoptosis of cet-r HSc3 cells. in addition, the Gal-3 inhibitor suppressed the growth of cet-r tumors. collectively, the results indicated that the Gal-3 inhibitor and cetuximab displayed a synergistic inhibitory effect on oScc tumors. in summary, the present study demonstrated that Gal-3 may serve an important role in cet-r oScc. The combination of cetuximab and the Gal-3 inhibitor may display a synergistic antitumor effect, thereby inhibiting the development of cetuximab resistance in OSCC.