This study evaluated the effects of 9% etidronic acid (HEBP) and 17% ethylenediaminetetraacetic acid (EDTA) used either with conventional syringe irrigation (CSI) or passive ultrasonic irrigation (PUI) on the fracture resistance of roots with different dentine thickness. The root canals of 120 extracted teeth were widened, leaving dentinal walls with different thicknesses of either 0.75 mm, 1.50 mm, or 2.25 mm with 40 teeth in each group. Within each of these groups, four subgroups (n = 10) were formed according to the final irrigation regimens applied: 2.5% NaOCl-17% EDTA with CSI; 2.5% NaOCl-17% EDTA with PUI; 2.5% NaOCl + 9% HEBP with CSI; 2.5% NaOCl + 9% HEBP with PUI. The irrigated root canals were obturated with AH Plus sealer and gutta-percha cones. A compressive vertical loading was applied to the samples and the force at fracture was recorded. Data were statistically analysed using a multiple linear regression analysis. The most influencing factor for the fracture strength of roots was the remaining dentine thickness, followed by the irrigation method, and then the irrigation solution. The samples irrigated using PUI were statistically significantly more resistant to fracture than those using CSI (mean difference = 116.3 N; 95% CI = [53.9, 178.6] N). The application of HEBP was associated with higher resistance to fracture than the application of EDTA (mean difference = 71.0 N; 95% CI = [8.6, 133.3] N).