The aim of this study was to investigate whether different fabrication processes, such as the computer-aided design/computer-aided manufacturing (CAD/CAM) system or the manual build-up technique, affect the fracture resistance of composite resin-based crowns. Lava Ultimate (LU), Estenia C&B (EC&B), and lithium disilicate glass-ceramic IPS e.max press (EMP) were used. Four types of molar crowns were fabricated: CAD/CAM-generated composite resin-based crowns (LU crowns); manually built-up monolayer composite resin-based crowns (EC&B-monolayer crowns); manually built-up layered composite resin-based crowns (EC&B-layered crowns); and EMP crowns. Each type of crown was cemented to dies and the fracture resistance was tested. EC&B-layered crowns showed significantly lower fracture resistance compared with LU and EMP crowns, although there was no significant difference in flexural strength or fracture toughness between LU and EC&B materials. Micro-computed tomography and fractographic analysis showed that decreased strength probably resulted from internal voids in the EC&B-layered crowns introduced by the layering process. There was no significant difference in fracture resistance among LU, EC&B-monolayer, and EMP crowns. Both types of composite resin-based crowns showed fracture loads of >2000 N, which is higher than the molar bite force. Therefore, CAD/CAM-generated crowns, without internal defects, may be applied to molar regions with sufficient fracture resistance.