The aim of this study was to investigate the effects of different post and core systems, CAD/CAM crown placement on fracture strength of endodontically treated mandibular premolar teeth. One hundred forty single-rooted premolar teeth were randomly divided into a control group and six experimental groups as follows: control group (Group 1); FiberSite post luting with Clearfil DC Core Plus (Group 2); RelyX Fiber post luting and core build up with Clearfil DC Core Plus (Group 3); RelyX Fiber post luting with Clearfil DC Core Plus and core build up with Filtek Bulk Fill Posterior (Group 4); specimens that received CAD/CAM crowns after the same procedures performed in Groups 2, 3, and 4, respectively (Groups 5, 6, and 7). Fracture strength tests were performed, and the failure modes were recorded. Data were statistically analyzed using one-way ANOVA and post hoc Tukey tests. The highest fracture resistance was observed in the control group and among the experimental groups in Group 4. Groups 3 and 5 showed similar fracture resistance followed by Group 2. The lowest fracture resistances were seen in the samples of Groups 6 and 7. While the fracture strength of Group 2 increased after the crown placement (Group 5), the fracture strength of Group 3 and Group 4 decreased (P < 0.05). While the specimens in Groups 1, 2, 3, and 4 predominantly showed favorable failure, unfavorable failure was more frequent in Groups 5, 6, and 7.