Oral squamous cell carcinoma (OSCC) is the most common cancer of the oral cavity. Curcumin (Cur), a naturally derived compound, is reported to have broad-spectrum anticancer activity and is considered as an effective nuclear factor-kappa B (NF-kappa B) inhibitor. The present study aimed to clarify the detailed molecular mechanism though which Cur regulates NF-kappa B pathway activity in OSCC. The viability of HSC3 and CAL33 cells following treatment with Cur was determined using a Cell Counting Kit-8 assay. The protein and mRNA expression of specificity protein 1 (Sp1), p65 and heat shock factor 1 (HSF1) was determined by western blotting and reverse transcription-quantitative PCR analysis, respectively. The NF-kappa B activity was measured by Dual-Luciferase reporter assay. Short hairpin RNA targeting Sp1 or control RNA was transfected into HSC3 cells using X-treme GENE HP DNA Transfection System. Colony formation assays were performed using crystal violet staining. The results demonstrated that Cur significantly inhibited the viability and colony formation ability of HSC3 and CAL33 cells. In addition, Cur decreased the expression of Sp1, p65 and HSF1 by suppressing their transcription levels. Cur decreased NF-kappa B activity in OSCC cells, and Sp1 downregulation enhanced the effect of Cur. The findings from the present study suggested that Cur may inhibit the proliferation of OSCC cells via a Sp1/NF-kappa B-dependent mechanism.