Aim: The aim of this study was to evaluate the influence of different endodontic materials and final irrigation regimens on vertical root fracture (VRF) resistance. Materials and Methods: Eighty human teeth were prepared then assigned into two groups (n = 40) according to the final irrigations. G1: 5 mL, 5.25% sodium hypochlorite (NaOCl), G2: 5 mL, 2% chlorhexidine gluconate (CHX). Each group was assigned into four subgroups according to the obturation system used (n = 10): A: iRoot SP/single gutta-percha cone (SGP), B: Only iRoot SP, C: Mineral trioxide aggregate (MTA)-Fillapex/SGP, D: AH26/SGP. The specimens were embedded in acrylic molds and subjected to compressive loading at a rate of 1 mm min until VRF occurred. Data were analyzed via three-way ANOVA tests. Results: The statistically significant difference was found among groups (P 0.05). The G1A and G1B and G1D revealed significantly higher-VRF values than G1C (P = 0.023). The roots filled with MTA-Fillapex revealed lower-VRF values than the other subgroups (P 0.05). Groups irrigated with NaOCl had significantly lower-VRF values than the groups irrigated with CHX (P 0.05). Conclusion: Final irrigation regimens could alter VRF resistance of root canals filled with different obturation technique and root canal sealers.