Objective: The aim of this study was to evaluate the in-vitro antimicrobial activity of Azadirachta indica (neem) and Salvadora persica (miswak) extracts as endodontic irrigants against Enterococcus faecalis in comparison to NaOCl solution. Materials and methods: Apical canal enlargement of 50 single-rooted teeth was performed up to size 40 K-file. Each root specimen was autoclaved in a glass tube containing 3 ml of brain heart infusion broth. Neem leaves and miswak extracts were prepared using absolute ethanol. After root canal infection with E. faecalis, samples were divided into five groups according to the type of solution used: normal saline (group A), NaOCl solution (group B), neem leaves extract (group C), miswak extract (group D) and a combination of NaOCl and neem leaves extract (group E). A microbiological sample was taken from each root canal and the number of bacterial colonies for E. faecalis was counted and expressed as colony forming units (CFU). Results: The number of CFU was statistically significant between groups (P = 0.001). The lowest mean value of CFU was noticed with group E. Conclusions: Neem leaf extract can be used as endodontic irrigant with an effective antimicrobial property against E. faecalis. The combination of herbs and chemical agents can produce a synergistic antimicrobial effect.