Dental pathogens lead to chronic diseases like periodontitis that causes loss of teeth. This research was to examine the plausible antibacterial efficacy of copper nanoparticles (CME-CuNPs) synthesized using Cupressus macrocarpa extract (CME) against periodontitis-causing bacteria. Moreover, antimicrobial properties of CME-CuNPs were assessed against oral microbes (M. luteus. B. subtilis, P. aerioginosa), which causes periodontal disease which was identified using morphological, biochemical analysis, and 16S-rRNA techniques. The CME-CuNPs were characterized by analysis techniques. Accordingly, the peak found at 577 nm using UV-vis spectrometer explained the formation of stable CME-CuNPs. Also, the results revealed the formation of spherical and oblong monodispersed CME-CuNPs with sizes ranged from 11.3 to 22.4 nm. The FTIR analysis suggested that the CME contains reducing agents. Consequently, they had a role in Cu reduction, and CME-CuNPs were formed. Furthermore, the CME-CuNPs exhibited potent antimicrobial efficacy against different isolates and it was superior to the reported values in literature. Antibacterial efficacy of CME-CuNPs upon testing bacteriawas compared to the synergistic solutionof clindamycin with CME-CuNPs. Particularly, synergistic solutions exhibited a superior capacity to prevent the selected bacterialgrowth. Minimum inhibitory concentration (MIC), Minimum bactericidal concentration (MBC), and FIC (Fractional Inhibitory Concentration) of CME-CuNPs with clindamycin recorded against the selected periodontal disease-causing microorganisms are observed between the range of 2.6-3.6 …