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Introduction Segmental bone defects (SBDs) are devastating injuries sustained by warfighters and are difficult to heal. Preclinical models that accurately simulate human conditions are necessary to investigate therapies to treat SBDs. We have developed two novel porcine SBD models that take advantage of similarities in bone healing and immunologic response to injury between pigs and humans. The purpose of this study was to investigate the efficacy of Bone Morphogenetic Protein-2 (BMP-2) to heal a critical sized defect (CSD) in two novel porcine SBD models. Materials and Methods Two CSDs were performed in Yucatan Minipigs including a 25.0-mm SBD treated with intramedullary nailing (IMN) and a 40.0-mm SBD treated with dual plating (ORIF). In control animals, the defect was filled with a custom spacer and a bovine collagen sponge impregnated with saline (IMN25 Cont, n = 8; ORIF40 Cont, n = 4). In experimental animals, the SBD was filled with a custom spacer and a bovine collage sponge impregnated with human recombinant BMP-2 (IMN25 BMP, n = 8; ORIF40 BMP, n = 4). Healing was quantified using monthly modified Radiographic Union Score for Tibia Fractures (mRUST) scores, postmortem CT scanning, and torsion testing. Results BMP-2 restored bone healing in all eight IMN25 BMP specimens and three of four ORIF40 BMP specimens. None of the IMN25 Cont or ORIF40 Cont specimens healed. mRUST scores at the time of sacrifice increased from 9.2 (±2.4) in IMN25 Cont to 15.1 (±1.0) in IMN25 BMP specimens (P Conclusions We have developed two porcine CSD models, including fixation with IMN and with dual-plate fixation. Porcine models are particularly relevant for SBD research as the porcine immunologic response to injury closely mimics the human response. BMP-2 restored healing in both CSD models, and the effects were evident within the first month after injury. These findings support the use of both porcine CSD models to investigate new therapies to heal SBDs.