In this article, the effects of cross-section and pitch on the mechanical response of NiTi endodontic files is studied by means of finite element analyses. The study was conducted over a set of eight endodontic rotary files, whose geometry was obtained from combinations of two cross-sections (square and triangular) and four pitches. Each file was subjected to bending and torsional analyses, simulating the testing conditions indicated in the ISO 3630 Standard, in order to assess their stiffness and mechanical strength. The results indicate that endodontic files with a square cross-section have double the stiffness of those with triangular cross-sections, both in terms of bending and torsion. For both loading modes, endodontic files with a triangular cross-section can undergo larger deformations before overload failure than those with a square cross-section: up to more in bending and in torsion. Moreover, under equivalent boundary conditions, endodontic files with triangular cross-sections present a higher fatigue life than those with square cross-sections: up to more than higher for small pitches. The effect of pitch on the stiffness and strength of the file is smaller than that of the cross-section shape, but smaller pitches could be beneficial when using a triangular cross-section, as they increase the bending flexibility, fatigue life, and torsion stiffness. These results suggest a clinical recommendation for the use of files with a triangular-shaped cross-section and a small pitch in order to minimize ledging and maximize fatigue life. Finally, in this study, we reveal the sensitivity of the orientation of files with respect to the bending direction, which must be taken into account when designing, reporting, and interpreting test results under such loading conditions.