(1) Background: The long-term survival of an endodontically treated tooth depends on a successful root canal treatment as well as an adequate definitive coronal restoration. This study aimed to evaluate the strength of endodontically treated premolars with mesial-occlusal-distal (MOD) cavity preparation restored with different direct coronal restoration materials but from the same manufacturer against fracture. (2) Methods: sixty intact premolars were selected and placed into five groups (n = 12): G1-intact teeth, G2-endodontic treatment and unrestored MOD cavities, G3-endodontic treatment and MOD cavities restored with Tetric PowerFlow and Tetric EvoCeram, G4-endodontic treatment and MOD cavities restored with Multicore Flow and Tetric EvoCeram, and G5-endodontic treatment and MOD cavities restored with Multicore Flow. The specimens were subjected to an axial compression load at a speed of 1.6 mm/min and optically inspected before and after with a stereomicroscope. For each premolars group, the following data were recorded: the compression resistance, the compressive strength, and the maximum force supported. The microstructure of the samples after the compression test was analyzed using scanning electron microscopy (SEM). (3) Results: statistical analysis (ANOVA and Tukey test) showed that there was a statistically significant difference between G1 and the other groups. Even though there was no statistically significant difference between the restored groups, a better mechanical behavior was registered within the G3. (4) Conclusions: this in vitro study indicated that none of the materials used can lead to a higher or at least similar fracture resistance as the intact teeth. The coronal restoration only with nano-hybrid composites may lead to a higher therapeutic benefit for the fracture-susceptible premolars.