<p>The structural integrity of layered VOPO₄ frameworks critically determines their electrochemical performance in aqueous zinc-ion batteries, yet the highly ordered stacking of VOPO₄ renders it susceptible to lattice stress accumulation and chemo-mechanical degradation during cycling, causing rapid capacity fading and a shortened battery lifespan. Herein, we show a strategy to alleviate these limitations through partial metal substitution in the VOPO₄ lattice, enabling the modulation of local coordination environments and mitigating lattice and cycling induced stress. As a proof-of-concept, theoretical calculations and experimental validation on Mn-substituted VOPO₄ reveal shortened M–O bond along the c-axis and the formation of Mn–O–P–O–V delocalized structure. These modifications introduce subtle lattice distortions and generate percolation channels that enable more facile, ordered Zn²⁺ migration, facilitating uniform lattice stress distribution. Real-time monitoring of interfacial stress during cycling identifies that Mn incorporation induces electronic redistribution and lattice anisotropy, promoting balanced intra-layer (a/b-axis) stress accommodation. Therefore, Mn-substituted VOPO₄ exhibits higher specific capacity and cycling stability, with 91.0% capacity retention over 2000 cycles at 1 A g⁻¹. This intra-layer anisotropy engineering strategy offers a practical route for mitigating dissolution and strain effects during cycling, paving ways for the development of high-energy-density positive electrodes with cycling durability.</p>