It is well established that efflux pumps play important roles in bacterial pathogenicity and efflux inhibitors (EIs) have been proved to be effective in suppressing bacterial virulence properties. However, little is known regarding the EI of Streptococcus mutans, a well-known caries-induced bacterium. In this study, we identified EI of S. mutans through ethidium bromide (EtBr) efflux assay and investigated how EI affected S. mutans virulence regarding cariogenicity and stress response. Results indicated that reserpine, the identified EI, suppressed acid tolerance, mutacin production, transformation efficiency of S. mutans, and modified biofilm architecture and extracellular polysaccharide distribution. Suppressed glycosyltransferases (Gtfs) activity was also noted after reserpine exposure. The data from qRT-PCR demonstrated that reserpine significantly altered the expression profile of quorum sensing and virulence associated genes. These findings suggest that reserpine represents a promising adjunct anticariogenic agent in that it suppresses virulence properties of S. mutans.