Objective: The aim of this in vitro investigation is to study the effect of endodontic cavity design on interfacial voids, class II resin composite sealing ability, and fracture resistance in mandibular premolars. Methods: A total of 48 single-rooted mandibular premolars received compound class II preparations with either traditional flare access cavities (group A) or contracted endodontic cavity preparations (group B). Each study group was subdivided according to the coronal restoration into two sub-groups as α and β. In the α group, a microhybrid composite was used after etch-and-rinse bonding technique using an MDP-containing universal adhesive. In the β group, a self-adhesive composite was used as coronal restoration after endodontic treatment (n = 12) for each subgroup. A micro-CT analysis was performed to assess the obturation interfacial voids and tracing of class II cervical interfacial adaptation. The tooth fracture resistance testing was then performed adding an extra group of 12 sound non-prepared teeth, which were tested as the control for fracture strength testing. A one-way ANOVA and post-hoc testing were used together with descriptive statistics for an analysis of the mean values of obturation interfacial voids. A two-way ANOVA was used to assess the fracture resistance test results, and to find the influence of endodontic access design and the type of composite material on the fracture resistance testing. Chi-square testing was employed to analyze the cervical interfacial seal of the class II restorations. Results: A one-way ANOVA revealed that there were no statistically significant differences between test groups in the amount of obturation interfacial voids (p > 0.05). There were no statistically significant differences between test groups in terms of cervical interfacial sealing ability (p > 0.05). A two-way ANOVA revealed that no statistically significant differences between test groups including the control group existed in terms of the fracture resistance testing (p > 0.05). Conclusions: Although it does not improve tooth fracture resistance, the contracted endodontic access cavity does not deteriorate the quality of obturation in terms of the interfacial porosity. The self-adhesive composite does not improve the efficiency of cervical interfacial adaptation or tooth fracture resistance regardless of the endodontic access cavity shape, yet it revealed a substantial load-bearing capacity.