A patient-specific 3D-printed titanium mandibular implant was developed with an integrated refillable drug storage tank to enable localized cisplatin release. The tank surface geometry and hydrogel formulation were optimized using the Taguchi method and incorporated into anatomically matched implants. In vivo evaluation in six porcine mandibular defect models demonstrated systemic safety over 12 weeks, with plasma platinum levels reduced by more than 60% compared to systemic administration. Hematological and biochemical indicators—including white blood cell count, liver enzymes, and renal function markers—remained within normal ranges throughout the observation period, confirming physiological stability and biocompatibility. No significant complications or implant loosening were observed. Functional validation was further performed on three representative human mandibular large defect models. Finite element analysis revealed implant stresses well below the yield strength of Ti6Al4V (<40%), and four-point bending fatigue tests confirmed structural endurance beyond 1 million loading cycles. This study provides the first functional and biocompatible patient-specific mandibular implant with integrated, refillable drug release, offering a clinically translatable strategy for simultaneous reconstruction and localized chemotherapy in head and neck oncology.