This systematic review aimed to evaluate whether cross-sectional geometry is associated with cyclic fatigue resistance of nickel–titanium (NiTi) endodontic instruments and to identify the geometric and materials-related features most frequently associated with improved fatigue performance. The protocol was prospectively registered on the Open Science Framework (OSF). PubMed, Scopus, Embase, Web of Science, and WorldCat were searched in April 2026 in accordance with PRISMA 2020. Eligible studies were comparative in vitro investigations that explicitly evaluated cross-sectional geometry or a related geometric parameter as a prespecified study factor and reported quantitative cyclic fatigue outcomes. Of 107 screened records, 66 full-text reports were assessed and 23 studies were included in the qualitative synthesis. Twenty-two studies had a medium risk of bias and one had a low risk of bias according to the Quality Assessment Tool for In Vitro Studies (QUIN). Cyclic fatigue resistance was most often reported as time to fracture or number of cycles to failure. Instruments with reduced metal mass, smaller core volume, lower cross-sectional area, and greater flexibility tended to demonstrate higher fatigue resistance in curved canals. S-shaped and double-S-shaped cross-sections were most consistently associated with favorable outcomes; however, this association is more plausibly related to reduced bending stiffness and canal-wall contact forces than to increased intrinsic material fatigue strength. Flat-side designs did not show a consistent advantage. The evidence was limited by heterogeneous testing protocols and residual confounding by alloy, heat treatment, taper, manufacturing, surface condition, and kinematics. No meta-analysis or quantitative dimensional correlation was feasible because testing conditions and detailed geometric parameters were inconsistently reported.