Streptococcus mutans is one of the major pathogens of dental caries. Oxyresveratrol, a natural compound found in plants, exerts inhibitory effects on many bacterial species but its effect on S. mutans is unknown. The objective of this study was to clarify the antibacterial effect of oxyresveratrol on S. mutans, including effects on basic viability, acidogenicity, acidurity, and extracellular polysaccharide synthesis. The expression of nine genes that encode virulence and protective factors in S. mutans was measured by qRT-PCR. Oxyresveratrol showed a dose-dependent inhibitory effect on survival of S. mutans. At 250 μg ml , oxyresveratrol reduced the S. mutans survival rate, inhibited synthesis of water-insoluble glucans, compromised biofilm formation, and significantly down-regulated the expression of glucosyltransferase-I (gtfB) and glucosyltransferase-SI (gtfC). However, the enzymatic activity of lactate dehydrogenase protein was increased and the expression of lactate dehydrogenase (ldh) and ATP synthase subunit beta (atpD) genes were also up-regulated. Besides, glucosyltransferase S (gtfD) up-regulation indicated that water-soluble glucan synthesis was promoted. The vicR, liaR, and comDE genes, which exert a self-protective function in response to external stress, were also up-regulated. In conclusion, oxyresveratrol inhibited the growth of S. mutans and also reduced biofilm formation, acid production, and synthesis of water-insoluble glucans by this organism. In addition, oxyresveratrol also activated a series of S. mutans self-protection mechanisms.