Salvadora persica sticks are used for chewing and oral-hygiene measures worldwide. The growth inhibition and anti-biofilm effects of various extracts on cariogenic Streptococcus mutans isolates were evaluated. Biofilm inhibition, gas chromatography-mass spectrometry (GC-MS) analyses for phytochemicals and their possible mode of interaction with biofilm response regulators were revealed using LigandFit docking protocols. All S. persica extracts showed considerable inhibitory activity and the cariogenic S. mutans showed varied susceptibility when compared with controls. The percentage reduction in biofilm inhibition obtained for methanol, ethanol, chloroform, acetone, and aqueous extracts were 87.92%, 85.75%, 72.44%, 61.66% and 58.68%, respectively. GC-MS analyses revealed >28 compounds, of which benzyl (6Z,9Z,12Z)-6,9,12-octadecatrienoate, 3-benzyloxy-1-nitro-butan-2-ol and 1,3-cyclohexane dicarbohydrazide interacted efficiently with the bacterial communication quorum-sensing (QS) regulators Streptococcus OmpP and Staphylococcus Lux proteins. The bioactive, dual-function, anti-biofilm agents in S. persica not only inhibit growth, but also control the colonization and accumulation of caries-causing S. mutans.