Piper aduncum has been widely used for medicinal purposes, and it has also been known to possess antimicrobial activity. Dental plaque is a complex ecosystem that harbors benign and pathogenic bacteria. It is desirable that compounds targeted to treat dental plaque-related diseases should be selective in their action, preserving the benign bacteria and inactivating the pathogenic ones. Thus, the study evaluated the antibacterial activity of P. aduncum leaf extracts against cariogenic (Streptococcus mutans) and health-associated (Streptococcus sanguinis) bacterium. For this, ethanol extracts were obtained by decoction, maceration, Soxhlet or turbo-extraction. The minimum inhibitory concentration (MIC) of the extracts was determined using the broth microdilution method. The influence of extracts on virulence traits of S. mutans was evaluated by the adherence assay to glass surface and by the glycolytic pH drop assay. S. mutans was more susceptible to crude extracts of P. aduncum than S. sanguinis and the highest activity was obtained with the maceration extract (MAC). Thus, MAC was further fractionated by gel permeation chromatography and the most active fraction against S. mutans (MIC of 0.08 mg/mL) had a MIC of 0.62 mg/mL for S. sanguinis. In addition, this fraction inhibited sucrose-dependent adherence of S. mutans and also reduced the level of acid production by this bacterium. The preferential activity of P. aduncum extracts towards S. mutans compared with S. sanguinis, in addition to their ability to inhibit sucrose-dependent adherence and reduce the level of acid production by S. mutans, suggest that this plant may have a potential to prevent dental caries.