The objective of the study was to evaluate the effect of access cavity design on fracture resistance of the extracted maxillary first and second molars prepared with three minimally invasive files.One hundred and twelve extracted human maxillary molars were selected for the study and divided randomly into three groups according to different minimally invasive files used (self-adjusting files [SAF], XP-endo Shaper [XP], and 4 V-Taper 2H [VT]) and one control group (CG). All experimental groups were subdivided into two subgroups, i.e., conservative access cavity (CAC) and traditional access cavity (TAC). All the canals in different experimental groups were enlarged up to apical size 30. The data were analyzed using the analysis of variance and Post hoc Tukey tests (P < 0.05).The highest mean fracture resistance of teeth with CAC was of the CG (1399.957), followed by teeth with CAC instrumented by SAF (1378.314) and XP-endo Shaper (1202.929). The least value was of the V-Taper file system (937.157). Furthermore, the highest mean fracture resistance value of teeth with TAC was of the CG (1143.171), followed by teeth with TAC instrumented by SAF (1150.607) and then XP-endo Shaper (998.150). The least value was of the V Taper file system (757.050).Conservative endodontic access (CAC) in the maxillary molars had shown significantly increased fracture resistance over TAC. SAF showed the maximum fracture resistance, while V-Taper files showed the least fracture resistance among the experimental groups compared.