Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) serve as effectors in the antitumor response. High mobility group nucleosomal binding domain 2 (HMGN2) is a candidate effector molecule involved in CTL and NK cell function. In the current study, recombinant human HMGN2 was isolated and purified from transformed Escherichia coli. Tca8113 cells, an oral squamous cell carcinoma line, were treated with a variety of HMGN2 protein concentrations and cell growth was analyzed. HMGN2 significantly inhibited the growth of Tca8113 cells and was predicted to arrest cells in the S phase. Moreover, HMGN2 treatment increased the apoptosis rate of Tca8113 cells. Western blotting indicated the upregulation of p53 and Bax proteins, whereas Bcl-2 was significantly downregulated. In addition, caspase‐3 was found to be activated. Furthermore, the HMGN2 protein may suppress the growth of Tca8113 cells in vivo. The results of the current study indicated that the HMGN2 protein may inhibit the growth of oral squamous cell carcinoma and HMGN2 may represent an antitumor effector molecule of CTL or NK cells.