Mandibular reconstruction with free fibular flaps is frequently used to restore segmental defects. The osteosythesis, including locking and non-locking plate/screw systems, is essential to the mandibular reconstruction. Compared with the non-locking system that requires good adaption between plate and bone, the locking system appears to present a better performance by locking the plate to fixation screws. However, it also brings about limitations on screw options, a higher risk of screw failure, and difficulties in screw placement. Furthermore, its superiority is undermined by the advancing of patient-specific implant design and additive manufacturing. A customized plate can be designed and fabricated to accurately match the mandibular contour for patient-specific mandibular reconstruction. Consequently, the non-locking system seems more practicable with such personalized plates, and its biomechanical feasibility ought to be estimated. Finite element analyses of mandibular reconstruction assemblies were conducted for four most common segmental mandibular reconstructions regarding locking and non-locking systems under incisal biting and right molars clenching, during which the influencing factor of muscles’ capacity was introduced to simulate the practical loadings after mandibular resection and reconstruction surgeries. Much higher, somewhat lower, and similar maximum von Mises stresses are separately manifested by the patient-specific mandibular reconstruction plate (PSMRP), fixation screws, and reconstructed mandible with the non-locking system than those with the locking system. Equivalent maximum displacements are identified between PSMRPs, fixation screws, and reconstructed mandibles with the non-locking and locking system in all four reconstruction types during two masticatory tasks. Parallel maximum and minimum principal strain distributions are shared by the reconstructed mandibles with the non-locking and locking system in four mandibular reconstructions during both occlusions. Conclusively, it is feasible to use the non-locking system in case of patient-specific mandibular reconstruction with fibular free flaps based on the adequate safety, comparable stability, and analogous mechanobiology it presents compared with the locking system in a more manufacturable and economical way.