Objectives: The aim of this study was to compare the cleaning efficacy of different final irrigation regimens in canal and isthmus of mandibular molars, and to evaluate the influence of related variables on cleaning efficacy of the irrigation systems. Materials and Methods: Mesial root canals from 60 mandibular molars were prepared and divided into 4 experimental groups according to the final irrigation technique: Group C, syringe irrigation; Group U, ultrasonics activation; Group SC, VPro StreamClean irrigation; Group EV, EndoVac irrigation. Cross-sections at 1, 3 and 5 mm levels from the apex were examined to calculate remaining debris area in the canal and isthmus spaces. Statistical analysis was completed by using Kruskal-Wallis test and Mann-Whitney U test for comparison among groups, and multivariate linear analysis to identify the significant variables (regular replenishment of irrigant, vapor lock management, and ultrasonic activation of irrigant) affecting the cleaning efficacy of the experimental groups. Results: Group SC and EV showed significantly higher canal cleanliness values than group C and U at 1 mm level (p < 0.05), and higher isthmus cleanliness values than group U at 3 mm and all levels of group C (p < 0.05). Multivariate linear regression analysis demonstrated that all variables had independent positive correlation at 1 mm level of canal and at all levels of isthmus with statistical significances. Conclusions: Both VPro StreamClean and EndoVac system showed favorable result as final irrigation regimens for cleaning debris in the complicated root canal system having curved canal and/or isthmus. The debridement of the isthmi significantly depends on the variables rather than the canals.