Introduction: Onlays are conservative restorations for posterior teeth that cover one cusp or more. Objectives: The aim of this study was to evaluate fatigue behavior and stress distribution in mandibular molars with different onlays and preparation designs under static and cyclic conditions, using finite element analysis. Material and methods: A model of a mandibular molar was obtained from a CBCT image. Mesio-occluso-distal cavities were presented with conservative and extensive buccolingual widths of the occlusal cavity. Buccal and lingual cusps were reduced. Therefore, onlays that covered buccal cusps and onlays that covered all cusps designs were obtained. All onlays were produced from three materials: lithium disilicate ceramic (LDS), polymer-infiltrated ceramic network (PICN), and zirconia ceramic. Safety factor was calculated and stress distribution was analyzed according to von Mises and maximum principal stress theories under static and cyclic conditions. Results: Cyclic loading caused higher stresses than static loading. The safety factor of zirconia and LDS onlays was higher than 1, except for conservative preparation with all-cusp coverage. PICN showed the lowest values of safety factors and the highest stress concentration in the dental tissues, which was associated with the least stresses in onlays. LDS and zirconia ceramic onlays showed lower stress concentration in dental structures than PICN. Conclusions: Loading conditions affected the results of stress in all models. Zirconia ceramic could be a suitable choice to restore mandibular molars, while PICN onlay might be an inappropriate restoration in terms of safety factors and stress distribution in restored dental structures.