The synthesis of single-atom catalysts (SACs) under mild conditions remains challenging due to the difficulty in controlling precursor dissociation and preventing metal atom aggregation. Here, we present a piezoelectricity-driven "strong-ligand substitution" strategy based on Pearson’s hard-soft acid-base principle. By enhancing ligand-metal and ligand-substrate interactions, we precisely regulate metal release kinetics, suppress migration, and achieve accurate anchoring of noble-metal single atoms (Au, Pt, Pd, Ru) on piezoelectric substrates (e.g., BiOCl, Bi₃Ti₄O₁₂) under mild conditions. Herein, the as-prepared SACs show markedly improved TOF values: Pt₁@CdS (photocatalytic H₂ evolution), Pt₁@BOC (piezocatalytic H₂ evolution), and Pd₁@Bi₃Ti₄O₁₂ (ammonia-borane hydrolysis) reach 33.9, 31.4, and 5.2 times those of their respective nanoparticle references, respectively. Using H₂PtCl₆·6H₂O as a model precursor, combined spectroscopic, mass spectrometric, NMR, and computational analyses reveal two distinct transformation pathways during piezoelectric reduction: in water, [PtCl₆]²⁻ is directly reduced to nanoparticles; in acetonitrile, piezoelectric activation induces nitrogen doping of the substrate and generates ·CN radicals that partially replace chloride ligands, forming [PtCl₂(CN)₂]²⁻. The high dissociation energy of CN slows metal release, while strong coordination with the N-doped substrate enhances anchoring stability, synergistically promoting efficient and stable Pt single-atom dispersion. Moreover, piezocatalysis is shown to critically impact Pt species formation and single-atom deposition site selectionThis work provides a mild synthesis route and elucidates the solvent and piezoelectric catalysis synergy in single-atom formation at the molecular level.