To screen small-molecule antibacterial drugs and investigate the antibacterial effect and mechanism of selective estrogen receptor modulators (SERMs) against Streptococcus mutans (S.mutans). The minimum inhibitory concentration of 426 Food and Drug Administration (FDA)-approved small-molecule drugs against S. mutans was determined using the microdilution method, and the target of SERMs acting on S. mutans was explored by employing a random transposon mutant library. Among the 426 FDA-approved SERMs, toremiphene, tamoxifen, clomiphene, and raloxifene exhibited excellent antibacterial effects against S.mutans. Results of mutant library screening showed that the two mutant strains were resistant to clomiphene. The gene sequence of the resistant strains showed that the transposon insertion sites were located in the genes of smu_546 and smu_874. SERMs, such as toremifene, tamoxifen, clomiphene, and raloxifene, exerted obvious antibacterial effects on S. mutans, and their targets may be proteins expressed by smu_546 and smu_874 gene.