Assembling natural proteins into large, strong, bone-mimetic scaffolds for repairing bone defects in large-animal load-bearing sites remain elusive. Here this challenge is tackled by assembling pure silk fibroin (SF) into 3D scaffolds with cortical-bone-like lamellae, superior strength, and biodegradability through freeze-casting. The unique lamellae promote the attachment, migration, and proliferation of tissue-regenerative cells (e.g., mesenchymal stem cells [MSCs] and human umbilical vein endothelial cells) around them, and are capable of developing in vitro into cortical-bone organoids with a high number of MSC-derived osteoblasts. High-SF-content lamellar scaffolds, regardless of MSC inoculation, regenerated more bone than non-lamellar or low-SF-content lamellar scaffolds. They accelerated neovascularization by transforming macrophages from M1 to M2 phenotype, promoting bone regeneration to repair large segmental bone defects (LSBD) in minipigs within three months, even without growth factor supplements. The bone regeneration can be further enhanced by controlling the orientation of the lamella to be parallel to the long axis of bone during implantation. This work demonstrates the power of oriented lamellar bone-like protein scaffolds in repairing LSBD in large animal models.