Objective: The purpose of this in vitro study was to assess the cuspal deflection of endodontically treated human premolars restored with different types of resin composites. Materials and methods: Forty-eight intact human upper premolars were selected, and standardized mesio-occluso-distal cavities were prepared and randomly divided into four experimental groups according to different direct restorative materials as follows (n = 12): Group I: Filtek Bulk Fill; Group II: SureFil SDR Flow + Ceram X Mono; Group III: GCeverX posterior + G-aenial posterior; and Group IV: Tetric N-Ceram. After storage in distilled water for 24 h at 37°C, specimens were subjected to thermocycling (5–55°C, ×1000). The cuspal deflection measurements were performed in microns at “after preparation”, “after endodontic treatment”, “24 h after restoration”, and “after thermocycling”. Data were statistically analyzed using Friedman and Kruskal Wallis tests (α = 0.05). Results: There were no statistically significant differences between groups in terms of cuspal deflection either after 24 hours or after thermocycling measurements (p >0.05). When comparing 24 hour and thermocycling cuspal deflection values within each restorative material group, none of the materials showed a significant difference (p >0.05). While no significant difference was detected between “after endodontic treatment” and “24 h after restoration” for each group (p >0.05), the difference between “after endodontic treatment” and “after thermocycling” cuspal deflection values increased statistically significantly for group II and group III (p <0.05). Conclusion: Endodontic treatment did not affect the cuspal movement of the upper premolars. Twenty-four hours after the restoration procedure and thermocycling procedure made no significant difference in the tested conventional/bulk-fill/bulk-fill flowable/fiber-reinforced resin composites’ cuspal deflection.