Exploring the molecular mechanism of oral squamous cell carcinoma (OSCC) pathogenesis is of great significance for its improvement and therapy. Non-structural maintenance of chromatin condensin I complex subunit G (NCAPG) is responsible for chromatin condensation and is associated with the progression of many malignant tumors. This study was aimed to investigate the role of NCAPG on OSCC pathogenesis. NCAPG mRNA expression data in OSCC tissues were obtained from the Gene Expression Omnibus (GEO) database and NCAPG protein expression in OSCC cell lines was determined by western blotting analysis. The results demonstrated that NCAPG expression in OSCC tissues and cells was higher than that of normal control. Following the short interfering RNA (siRNA) knockdown of NCAPG in two OSCC cell lines, we observed that NCAPG depletion notably inhibited OSCC proliferation and cell cycle progression, as well as promoted apoptosis in vitro. Besides, silencing of NCAPG specifically inhibited the GSK-3β/β-catenin signaling. Furthermore, we demonstrated that NCAPG was a downstream target of miR-378a-3p. NCAPG silencing counteracted the effect of the miR-378a-3p inhibitor on cell proliferation/cycle induction. Collectively, these findings suggest that NCAPG is crucial in OSCC progression and development, and may serve as a potential therapeutic target for OSCC.