Background: Intracanal medicaments have been used as adjuncts to ensure elimination of bacteria from the root canal complex. This study compared the antimicrobial potential of Khadira, Guggul, Triple antibiotic paste and Calcium hydroxide against oral microorganisms such as Enterococcus faecalis, Streptococcus mutans and Candida albicans. Materials and Methods: Antimicrobial activity assessment of the intracanal medicaments was done using the agar well diffusion assay. The zone of inhibition (in mm) was measured at both 50 & 100 mg concentrations. Results: The triple antibiotic paste exhibited the highest antimicrobial efficacy. However, the natural medicament Khadira demonstrated a greater zone of inhibition when compared to calcium hydroxide. Conclusion: Natural agents such as Khadira can be used an alternative to traditional intracanal medicaments to ensure microbial elimination and success in root canal therapy