Harmonic-structured (HS) metallic materials have attracted increasing attention due to their outstanding strength–ductility synergy. However, the grain-scale fracture mechanisms governing damage initiation and propagation in HS microstructures remain insufficiently understood, limiting the establishment of predictive design strategies for strength–toughness optimization. In this work, HS CoCrFeMnNi high-entropy alloys with systematically tailored fine-grain (FG) shell fractions were fabricated to elucidate intrinsic fracture-resistant mechanisms. Quasi in-situ tensile experiments combined with electron backscatter diffraction (EBSD) and crystal plasticity finite element–cohesive zone modeling (CPFEM–CZM) reveal that FG regions exhibit higher crack susceptibility due to pronounced strain gradients, particularly at coarse-grain (CG)/FG interfaces and within FG zones. These strain gradients evolve with increasing deformation and intensify local stress concentrations through deformation incompatibility, promoting preferential crack nucleation and early crack propagation. In contrast, CG regions display superior intrinsic deformability and enable sustained plastic energy dissipation. As cracks propagate into CG domains, the activation of multiple slip systems generates elevated geometrically necessary dislocation densities near crack tips, leading to enhanced back stress, crack blunting, and increased fracture tolerance. A critical FG fraction of 31.4% is identified, which effectively suppresses premature crack nucleation in FG regions while preserving high strength unattainable in low-FG HS counterparts. This optimized dual-phase synergy ensures an enhanced balance between strength and fracture resistance. The present study quantitatively elucidates the role of FG fraction in damage tolerance and establishes microstructural design principles for fracture-resistant architectured and high-entropy alloys.