Background <p>Root canal-treated teeth often exhibit significant structural loss, necessitating effective and conservative restorative techniques. The present study aimed to assess the effect of cavity design on the fracture resistance of endo-crown restorations.</p> Materials and methods <p>Thirty human mandibular first molars were carefully chosen based on a sample size estimation. All teeth underwent root canal treatment and were allocated into three groups (<i>n</i> = 10 each) according to the cavity design; conventional cavity design (group 1), conventional cavity design with a root canal extension (group 2), and conventional cavity design with a buccal groove (group 3). Following cementation of the endo-crown restorations and submission to thermo-mechanical fatigue, each group was subjected to fracture resistance testing and failure mode analysis. A one-way ANOVA and Tukey’s post hoc tests were conducted to compare the mean fracture load values, while the Chi-square test was used to compare failure modes among the study groups. The significance was set at 5% with a confidence interval (CI) of 95%.</p> Results <p>The conventional design demonstrated the highest fracture resistance, significantly outperforming the other designs (<i>P</i> &lt; 0.0001). The root canal extension design showed the lowest resistance, while the buccal groove design exhibited intermediate results (<i>P</i> &lt; 0.0001). Failure mode analysis revealed distinct patterns, indicating that the conventional design with root canal extension fractured under the lowest loads, yielded the most favorable outcomes (<i>P</i> &lt; 0.0001).</p> Conclusions <p>The choice of cavity design significantly impacts the mechanical performance of endo-crown restorations. Endo-crown restorations exhibited the highest fracture resistance in the conventional cavity design. Moreover, the design extending into a buccal groove can be preferred over the extension into the root canals.</p> Clinical significance <p>The findings support using conventional designs to boost the longevity and effectiveness of restorations in root canal-treated teeth. When additional extensions are required, a buccal groove extension is suggested rather than an extension into the root canal. This study contributes valuable insights for clinicians in selecting optimal restorative strategies for root canal-treated teeth.</p> Clinical trial number <p>Non-applicable. Conducting the current experiment was limited to the approval by the local Research Ethics Committee at the Faculty of Dentistry, Minia University, Egypt (committee no. 94, registration no. 705, dated 28 February 2023).</p>