Background This study evaluates the mechanical performance of deep margin elevation technique for carious cavities by considering the shape designs and material selections of inlay using a computational approach combined with the design of experiments method. The goal is to understand the effects of the design parameters on the deep margin elevation technique and provide design guidelines from the biomechanics perspective. Methods Seven geometric design parameters for defining an inlay’s shape of a premolar were specified, and the influence of cavity shape and material selection on the overall stress distribution was investigated via automated modelling. Material selection included composite resin, ceramic, and lithium disilicate. Finite element analysis was performed to evaluate the mechanical behavior of the tooth and inlay under a compressive load. Next, the analysis of variance was conducted to identify the parameters with a significant effect on the stress occurred in the materials. Finally, the response surface method was used to analyze the stress responses of the restored tooth with different design parameters. Results The restored tooth with a larger isthmus width demonstrated superior mechanical performance in all three types of inlay materials, while the influence of other design parameters varied with the inlay material selection. The height of the deep margin elevation layer insignificantly affected the mechanical performance of the restored tooth. Conclusions A proper geometric design of inlay enhances the mechanical performance of the restored tooth and could require less volume of the natural dentin to be excavated. Furthermore, under the loading conditions evaluated in this study, the deep margin elevation layer did not extensively affect the strength of the tooth structure.