Pb-based piezoelectric ceramics with excellent piezoelectric response and low dielectric loss are crucial for advanced applications but still challenging to achieve. Herein, an approach based on synergistic effect of defect engineering and localized heterogeneous structures was developed to prepare 0.11 Pb(In0.5Nb0.5)O3-0.89 Pb(Hf0.47Ti0.53)O3+xmol%(Sb5++Nd3+) advanced piezoelectric ceramics by solid phase reaction method. Effects of ion co-doping on physical phase structures, defect concentrations, and electric domain morphologies of ceramics were all investigated. A mapping relationship between defect concentration, formation of localized heterogeneous structure, and modulation of piezoelectric and dielectric properties of ceramics was extracted. Values of d33, TC, εr, tanδ (%), and kp of ceramics obtained at x = 0.4 mol% were determined as respectively 607 pC/N, 313.1°C, 3407.81, 1.42, and 0.66, showing excellent overall performances. The doping of (Sb5++Nd3+) skillfully modulated the concentration of defects inside ceramics, resulting in excellent piezoelectric response and reduced dielectric loss. On the other hand, lattice distortion induced by doping generated nanodomains formed localized heterostructures and significantly reduced the Gibbs free-energy barrier, resulting in excellent piezoelectric response and dielectric properties. These effects can mainly be attributed to synergistic action of defect engineering and localized heterostructures. Overall, proposed ceramics and strategy look promising for preparing Pb-based piezoelectric ceramics with excellent comprehensive performance.