Aim of the Study: The purpose of the study is to evaluate the occlusal relationship of the mesiobuccal cusp of a mandibular first molar with the marginal ridge of maxillary first molar and second premolar and to analyze the effect of the above occlusal relation on different direct and indirect restorations using finite element analysis (FEA). Methodology: Four hundred volunteers studying in a dental college were screened, of which 100 volunteers were selected for studying occlusal relationships based on the inclusion and exclusion criteria. The two most common occlusal relationships were considered for analyzing two direct (amalgam and direct composite restorations) and two indirect restorations (composite and ceramic restorations). Three-dimensional (3D) scanning of the models was performed, and Class II tooth preparations specific for each restorative material were prepared digitally on 3D models. FEA was employed to study von Mises (VM) stress, principal stresses, and cuspal deflection for each restorative material, and failure of the tooth-restoration unit was calculated using the modified Mohr failure criterion. Results: Among all the analyzed materials, cuspal deformation, principal stresses, and VM stresses were high for direct composite restoration and least for ceramic inlay. According to modified Mohr criteria, except for direct composite, all other materials performed better. Conclusion: Silver amalgam and ceramic restorations presented with minimal stress concentration and cuspal deflection, and Type I occlusal relationship presented with higher stress concentration compared to Type II.