The better understanding of the clinically important behavioral features of new instrument systems has an important significance for the clinical endodontics. This study aimed to investigate the shaping and centering ability as well as cyclic fatigue resistance of HyFlex CM (CM), HyFlex EDM (EDM) and EdgeFile (EF) thermally treated nickel–titanium (NiTi) endodontic instrument systems. Sixty curved root canals of the mesial roots of mandibular molars were randomly assigned into three groups (n = 20) and shaped using CM, EDM and EF files up to the size 40 and taper 04 of the instruments. µCT scanning of the specimens before and after preparation was performed and the morphometric 2D and 3D parameters were evaluated in the apical, middle and coronal thirds of root canals. In each group, 40.04 instruments (n = 20) were subjected to the cyclic fatigue resistance test in artificial root canals at 37 °C temperature until fractures occurred, and the number of cycles to failure (NCF) was calculated. The fractographic analysis was performed using a scanning electron microscope, evaluating topographic features and surface profiles of the separated instruments. The one-way analysis of variance with post hoc Tuckey’s test was used for statistical analysis of the data; the significance level was set at 5%. All systems prepared the comparable percentage of root canal surface with the similar magnitude of canal transportation in all root thirds (p > 0.05), but demonstrated significantly different resistance to cyclic fatigue (p < 0.05). The most resistant to fracture was EF, followed by EDM and CM. The length of the fractured fragments was not significantly different between the groups, and fractographic analysis by SEM detected the typical topographic features of separated thermally treated NiTi instrument surfaces.