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Aim: To evaluate the pulp tissue dissolution, antimicrobial action, and smear layer removal using an experimental irrigant combining Salvadora persica and sodium hypochlorite (NaOCl) with and without ultrasonic activation in comparison to standard irrigation protocol of NaOCl and ethylenediamine tetraacetic acid (EDTA) with and without ultrasonic activation. Materials and Methods: Pulp tissue dissolution - Pulp tissue weighing 0.9 g was dissolved in each experimental Group G1: 5 ml of 5% NaOCl, G2: G1 + ultrasonic activation, G3: 5 ml 5% NaOCl + 40% S. persica, G4: G3 + ultrasonic activation and weighed after 1, 5, and 10 min. The difference in weight of the tissue sample was assessed. Smear layer removal and calcium/phosphate (Ca/PO4) ratio - G1: 5 ml of 5% NaOCl, saline, 1 ml of 17% EDTA, G2: G1 + ultrasonic activation, saline, 17% EDTA, G3: 5 ml 5% NaOCl + 40% S. persica G4: G3 + ultrasonic activation. Each tooth was then split longitudinally and subjected to scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM-EDX) analysis. Antibacterial Activity- assessed against Enterococcus Faecalis. Statistical Analysis: SEM, pulp tissue dissolution and antimicrobial efficacy – Kruskal–Wallis and post hoc Mann–Whitney EDX – ANOVA and Tukey's honestly significant difference post hoc analysis. Results: Pulp dissolution by G3 and G4 was better. However, there was no statistically significant difference between the groups (P > 0.05). Experimental combination performed better in terms of smear layer removal, showed higher amount Ca/PO4 in EDX analysis, but the difference was not statistically significant between the groups (P > 0.05). G2 showed maximum antimicrobial efficacy compared to all groups but not statistically significant (P > 0.05). Conclusions: The combined formulation of 5% NaOCl + 40% S. Persica was as effective as conventional protocol and ultrasonic activation improved its efficacy.

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