Patient-specific mandibular reconstruction plates (PSMRPs) have gained prominence for their precise adaptation to mandibular contours and reported enhanced mechanical performance compared to the manual-bent mandibular reconstruction plates (MBMRPs). However, clinical adoption remains cautious due to insufficient biomechanical evidence directly and carefully comparing their performance. Hence, this study investigated the biomechanical behavior between two mandibular reconstruction assemblies with MBMRP and PSMRP, respectively. Mechanical properties of these two reconstruction systems, including yield and ultimate strength, fatigue strength and life, were evaluated through finite element analyses (FEA) and biomechanical tests, during which digital image correlation (DIC) was used to measure full-field displacements and strains. Results revealed that the PSMRP provides higher stiffness and longer fatigue life to the reconstruction system than the MBMRP, signified by above 33% higher stiffness in the quasi-static compression and exceeding 90% more life cycles in the cyclic test, respectively. These findings not only highlight the biomechanical advantages of PSMRP over MBMRP but also underline the strong correlation between FEA predictions and experimental outcomes in the mandibular reconstruction system, validating the FEA’s utility for preoperative biomechanical evaluation. Collectively, this work provides critical evidence supporting the biomechanical superiority of PSMRPs in mandibular reconstruction—potentially reducing risks of plate failure and reoperation—and establishes a translational framework that combines computational and experimental biomechanics to advance patient-specific implant design in oral, dental, and craniofacial surgery.