Due to the increasing variety of temporary restorative materials and the importance of the remaining crown structure in maintaining the fracture resistance of teeth. This study aimed to investigate the fracture resistance of temporary restorations in maxillary premolars undergoing various access cavities designs. This study was conducted on 110 extracted human upper premolars. The samples were divided into three groups as follows. Group A: the mesial-occlusal (MO) cavities (n = 33); Group B: the mesial-occlusal distal (MOD) cavities (n = 33); and Group C: the anatomically reduced cavity (n = 33), and one group of 11 negative controls. Then, each group was divided into three groups of 11 samples for restoration with three types of restorative material (Coltosol F, ENA Soft, GC Fuji II). The mean fracture resistance in MO, MOD, and reduced anatomical cavities groups was 230.64 ± 110.03, 148.11 ± 58.31, and 325.85 ± 137.29, respectively. There was a significant difference between different groups of the cavity design (P < 0.05), and reduced anatomical cavities had the greatest fracture resistance values (P < 0.05). Moreover, there was a significant difference in the fracture resistance of temporary materials in all three cavity design groups (P < 0.05). Coltosol F showed lower fracture resistance than ENA Soft and GC Fuji II temporary restorative materials. The present study showed that different cavity designs and restorative materials affect fracture resistance of maxillary premolars following the endodontic treatment. The anatomically reduced access cavities with ENA Soft for temporary restoration provide the highest fracture resistance.