(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.