Foreign body reaction (FBR) is a major obstacle to effective osseointegration in bone defect repair. The pore size of scaffolds is a key determinant of FBR; however, its impact on FBR remains controversial, with limited in vivo evidence. In this study, electrohydrodynamic-printed polycaprolactone (PCL) scaffolds with pore sizes of 100 μm, 200 μm, and 300 μm were fabricated to investigate their effects on macrophage polarization, FBR, and bone regeneration. In vitro experiments showed that the 300 μm group promoted M2 polarization of macrophages, reduced TNF-α expression (0.71- and 0.81-fold compared to the 100 μm and 200μm groups, respectively), and increased TGF-β1 expression (1.39- and 1.19-fold, respectively), thereby enhancing osteogenic gene expression in MC3T3-E1 cells (Runx2, COL-I, OCN). Finite element analysis and transcriptomics sequencing revealed that pore size-dependent changes in scaffold stiffness modulate Piezo1 activation, influencing macrophage polarization. In vivo experiments showed that the 300 μm group exhibited the thinnest fibrous capsule (0.78- and 0.79-fold compared to the 100 μm and 200 μm groups, respectively), enhanced angiogenesis, and achieved better bone regeneration, with increased bone volume/total volume and bone mineral density. These findings indicate that 300 μm pore-sized scaffolds promote bone regeneration by modulating macrophage polarization and attenuating FBR, providing a basis for optimized scaffold design and clinical translation in bone defect repair.