The reconstruction of large mandibular defects with optimal aesthetic and functional outcomes remains a major challenge for maxillofacial surgeons. The aim of this study was to design patient-specific mandibular reconstruction implants through a semi-automated digital workflow and to assess the effects of topology optimization on the biomechanical performance of the designed implants. By using the proposed workflow, a fully porous implant (LA-implant) and a topology-optimized implant (TO-implant) both made of Ti-6Al-4V ELI were designed and additively manufactured using selective laser melting. The mechanical performance of the implants was predicted by performing finite element analysis (FEA) and was experimentally assessed by conducting quasi-static and cyclic biomechanical tests. Digital image correlation (DIC) was used to validate the FE model by comparing the principal strains predicted by the FEM model with the measured distribution of the same type of strain. The numerical predictions were in good agreement with the DIC measurements and the predicted locations of specimen failure matched the actual ones. No statistically significant differences (p < 0.05) in the mean stiffness, mean ultimate load, or mean ultimate displacement were detected between the LA- and TO-implant groups. No implant failures were observed during quasi-static or cyclic testing under masticatory loads that were substantially higher (>1000 N) than the average maximum biting force of healthy individuals. Given its relatively lower weight (16.5%), higher porosity (17.4%), and much shorter design time (633.3%), the LA-implant is preferred for clinical application. This study clearly demonstrates the capability of the proposed workflow to develop patient-specific implants with high precision and superior mechanical performance, which will greatly facilitate cost- and time-effective pre-surgical planning and is expected to improve the surgical outcome.