This study aimed to examine the shaping ability of six rotary and reciprocating file systems, as well as hybrid techniques in simulated S-shaped root canals. A hundred and twenty S-shaped radiopaque thermosetting epoxy resin blocks were grouped according to the system used for biomechanical preparation. Six groups of 15 canals each were prepared using TruNatomy, Procodile, VDW Rotate, Hyflex CM, OneCurve, and WaveOne Gold, respectively. Two additional hybrid (Procodile/Hyflex CM and Procodile/TruNatomy) groups (n=15 each) were added after evaluating the results of individual systems. All canals were enlarged to 0.25 mm apically. Canal transportation, centering ability, diameter increase, and iatrogenic errors were assessed by superimposed pre-operative and post-operative images. AutoCAD was used for data analysis. All groups were statistically compared with analysis of variance and Tukey honest significant difference test (p<0.05). Hyflex CM resulted in the most conservative diameter increase in all thirds (coronal, middle, and apical; p<0.001). Procodile showed the best (p<0.001) centering ability in the coronal and middle thirds, while TruNatomy resulted in the least canal transportation and most centering preparation in the apical third (p<0.001). Hybridisation of Procodile and Hyflex CM produced the least canal transportation and best centering ability in the middle third (p<0.001). No instrument breakage occurred, and no ledge, elbow, or apical zip formation was observed during canal preparation. Hybridisation of Procodile and Hyflex CM showed remarkable results in preserving the canal diameter in all thirds and resulted in the least canal transportation and best centering ability in the middle third of the canal. However, when treatment cost and duration limit the clinical applicability of the hybrid technique, clinicians can use a single file system (Hyflex CM or TruNatomy) since it shows satisfactory results in all parameters when compared with a hybrid system.