Immunomodulatory biomaterials have emerged as promising treatment agents for bone defects. However, it is unclear how such biomaterials control immune cell behaviors to facilitate large-segment bone defect repair. Herein, we fabricated biphasic calcium phosphate ceramics with nanowhisker structures to explore the immunoregulation features and influence on large-segment bone defect repair. We found that the nanowhisker structures markedly facilitated large-segment bone defect repair by promoting bone regeneration and scaffold resorption. Our in vitro experiment and transcriptomic analysis showed that mechanical stress derived from nanowhisker structures may activate the transcription of Egr-1 to induce early switch of macrophage phenotype to M2, which could not only facilitate osteogenic differentiation of BMSCs but also enhance the expression of osteoclast differentiation-regulating genes of M2 macrophage. In vivo study showed that the nanowhisker structures relieved local inflammatory responses by inducing early switch of macrophage phenotype from M1 to M2, which resulted in accelerated osteoclastogenesis for biomaterial resorption and osteogenesis for ectopic bone formation. Hence, we presume that nanowhisker structures may orchestrate bone formation and material resorption coupling to facilitate large-segment bone defect repair by controlling the switch of macrophage phenotype. This study provides new insight into the designing of immunomodulatory tissue engineering biomaterials for treating large-segment bone defects.