The study aimed to assess the effect of two etidronate-containing irrigants and EDTA on the ability of sodium hypochlorite (NaOCl) to remove the smear layer and dissolve organic tissues. This study evaluated the following solutions: distilled water, 3% NaOCl, 3% NaOCl + EDTA, and 3% NaOCl mixed with etidronate powder from two manufacturers [Dual Rinse, (DR); IsraDent, (ID)] to obtain 9%, 15%, and 18% solutions. To assess the proteolytic activity, bovine muscle tissue samples (56.1 ± 5.4 mg; n = 10 per group) were immersed in the tested solutions for 15 min. Absolute weight changes and percentages of weight changes (wt%) were calculated. To assess smear layer removal, the root canals of human wisdom teeth were instrumented, irrigated with the tested solutions (n = 10 per group), and evaluated using SEM. Statistical analysis employed an ANOVA with a post-hoc Tukey test and paired t-test, the Kruskal–Wallis test with a pairwise Wilcoxon rank sum test, and the Friedman test with a pairwise Wilcoxon signed-rank test. The mean weight loss in the NaOCl group comprised 17.3 mg (32 wt%). Sequential use of NaOCl and EDTA resulted in a significant increase in proteolytic activity of the former (57 wt%), while mixing these solutions led to a reduction of proteolytic activity (17 wt%). All NaOCl/DR groups exhibited a significantly greater dissolution activity than that of NaOCl alone, with the mean weight loss ranging from 23.3 mg (40 wt%) to 24 mg (41 wt%). ID9% and ID15% significantly decreased the proteolytic activity of NaOCl. In most groups, the apical thirds of the root canals demonstrated a significantly heavier smear layer compared to the middle and coronal thirds. The most effective smear layer removal was observed after irrigation with NaOCl combined with EDTA or DR (all concentrations); however, in the NaOCl + EDTA and DR18% groups, it was accompanied by moderate to severe erosion. Irrigation with ID did not result in smear layer removal or dentin erosion. In conclusion, the smear layer removal and pulp dissolving effects of continuous chelation using etidronate were manufacturer/composition-dependent. DR9% combined with NaOCl demonstrated the most promising results.