Biofilm is the advantageous mode of growth for microorganisms, where dynamic microbial communities are irreversibly attached to a solid substratum, as well as to each other. The residing bacterial cells in the biofilm embedded in a self-made matrix of extracellular polymeric substances, which makes the community up to 1,000-times more resistant to detergents and antibiotics than planktonic cells. Dental caries is a common oral infectious disease associated with pathogenic microbes, such as Streptococcus mutans, which integrated into a complex dental plaque biofilm on tooth surface. Streptococcus mutans has been shown to be one of the main pathologic organisms in the initiation and development of dental caries because of the following virulence attributes: producing glucosyltransferases, and synthesizing extracellular polysaccharides, which promote bacterial accumulation and biofilm formation, surviving at a low pH environment and rapidly producing organic acids. The extracellular polysaccharides matrix constitutes an external scaffold system that supports stable synergistic interactions between cariogenic bacteria and commensal. The increased prevalence of antibiotic resistance exhibited by biofilm bacteria prompts an emergent need to develop new drugs and to design novel strategies to identify effective drug targets. As the attachment of the cells to a surface is crucial for Streptococcus mutans biofilm formation, it became an attractive target for researchers to design successful small molecule inhibitors. Numerous small molecules and natural products, including marine alkaloid, flavonoids, anthraquinones, phenolic compounds, and other synthetic analogs have been characterized and shown to have anti-biofilm activity toward Streptococcus mutans. In this review, we briefly summarized their chemical properties, mode of action and biological efficacy of different small molecules reported.