Intracanal medicament is an important step in reducing the microorganisms in root canals. Drug synergism occurs when two or more drugs work together to produce an effect more potent than if each drug were applied individually. E. faecalis and C. albicans are the most common microorganisms responsible for root canal treatment failure. The current study aimed to determine the antimicrobial efficacy of AgNps, PrNps, and their combination against E. faecalis and C. albicans, to determine the effect of their combination on the adherence and hydrophobicity of E. faecalis and C. albicans on the tooth surface and to study the effect of their combination on proliferation and expression of vascular endothelial growth factor (VEGF) from PDLSCs. The antimicrobial efficacy was studied by colony forming unit method and adherence assay was assessed by fluorescence microscopy. To measure the cell proliferation, MTT assay was performed and VEGF concentration was measured by ELISA. The synergisms (combination) of AgNps and PrNps have similar antimicrobial efficacy compared to AgNps and PrNps alone. The synergisms had least hydrophobicity and adherence values compared to AgNps and PrNps alone. PDLSCs viability treated with combination of AgNPs and PrNPs showed better cell viability compared to AgNPs, PrNps alone and CHX. VEGF plays a pivotal role in improving the angiogenesis and osteogenesis for regeneration. Synergisms (combination) of the of AgNps and PrNps improve the VEGF secretion compared to the AgNPs, PrNps alone and CHX. The combination of AgNps and PrNps can be used as potent intracanal medicament.