This work used the broth microdilution method to investigate the antimicrobial activity of the essential oil obtained from the leaves of Plectranthus neochilus (PN-EO) against a representative panel of oral pathogens. We assessed the antimicrobial activity of this oil in terms of the minimum inhibitory concentration (MIC). PN-EO displayed moderate activity against Enterococcus faecalis (MIC = 250 μg/mL) and Streptococcus salivarus (MIC = 250 μg/mL), significant activity against Streptococcus sobrinus (MIC = 62.5 μg/mL), Streptococcus sanguinis (MIC = 62.5 μg/mL), Streptococcus mitis (MIC = 31.25 μg/mL), and Lactobacillus casei (MIC = 31.25 μg/mL), and interesting activity against Streptococcus mutans (MIC = 3.9 μg/mL). GC-FID and GC-MS helped to identify thirty-one compounds in PN-EO; α-pinene (1, 14.1%), β-pinene (2, 7.1%), trans-caryophyllene (3, 29.8%), and caryophyllene oxide (4, 12.8%) were the major chemical constituents of this essential oil. When tested alone, compounds 1, 2, 3, and 4 were inactive (MIC > 4000 μg/mL) against all the microorganisms. These results suggested that the essential oil extracted from the leaves of Plectranthus neochilus displays promising activity against most of the evaluated cariogenic bacteria, especially S. mutans.