OBJECTIVES: Large mandibular defects present challenges for bone regeneration. This pilot study evaluates the safety and preliminary efficacy of direct electrical stimulation (ES) on tissue healing in a preclinical model, testing whether ES can enhance bone formation in critical-size mandibular defects. MATERIALS AND METHODS: Six adult mini pigs with critical-size mandibular defects were used in a split-mouth design. The test group (n = 6) received 0.5 V AC/20 Hz ES for 3 × 45 min daily over three weeks, while the control group (n = 6) had no stimulation. Safety, early bone growth, and soft tissue effects were assessed at three locations: S1 (cancellous bone interface), S2 (middle of the defect), and S3 (pristine dense bone). RESULTS: The ES group showed no adverse effects, confirming implant safety. The ES group exhibited significantly higher bone formation, particularly in S2 and S3. Enhanced vascularization and immune response, in terms of increased mast cells, were also observed in S2. CONCLUSIONS: The implant device with ES is safe and promotes bone formation and vascularization in select sub-regions (S2 and S3). However, ES alone may not suffice for complete bone regeneration in critical-sized defects, and further optimization is needed. CLINICAL RELEVANCE: This study demonstrates the potential of ES to improve bone healing in large mandibular defects, offering insights for clinical use in maxillofacial reconstruction.