This in vitro study aims to assess the cyclic fatigue resistance of the Protaper Ultimate (PTU) files compared to the Protaper Gold (PTG) and the M3 UDG (M3) files using various motion kinematics in simulated canals. As far as the authors are aware, no study has previously compared the three file systems before this current investigation. Therefore, closing this information gap is the goal of the current research. Methods: A total of (60 new endodontic files were randomly divided into 6 groups (10 files per group); groups 1, 3, and 5 used continuous rotation (CR), while groups 2, 4, and 6 used forward reciprocating motion (FRM). A manufactured stainless-steel artificial canal was used to perform the cyclic fatigue testing. The results were analyzed using Student’s t-test and two-way ANOVA. All pairwise comparisons revealed statistically significant differences in the time to failure (TTF) for every study group (p < 0.001), with the exception of the PTG and M3 files, which performed similarly using both CR and FRM. Conclusions: The PTU files performed better than the PTG and M3 files in terms of the TTF and number of cycles to failure (NCF) using both CR and FRM.