<p>This study develops an effective molecular isomerization strategy to enhance photocatalytic hydrogen peroxide (H₂O₂) production by leveraging the structural tunability of benzobisthiazole (BT)—an electron-deficient planar heterocycle with superior optoelectronic properties and chemical stability. Unlike conventional isomeric covalent organic frameworks (COFs) which focus on symmetric or unidirectional conjugation systems, we exploit the two orthogonal <i>π</i>-conjugation pathways (2,6- versus 4,8-substitution) of BT to construct regioisomeric COFs with distinct topological connectivity, a design that remains rarely explored for photocatalytic H₂O₂ generation. Utilizing subsitution-position flexibility of BT, two regioisomeric monomers, namely 2,6-BT-CHO and 4,8-BT-CHO_pro, were designed and polymerized into highly crystalline donor-acceptor (D-A) covalent organic frameworks (COFs): 2,6-BT-COF and 4,8-BT-COF. These COFs exhibit high surface areas, extended <i>π</i>-conjugation, and excellent light-harvesting capabilities, rendering them ideal photocatalysts. Remarkably, under visible-light irradiation in pure water, 2,6-BT-COF achieved a H₂O₂ production rate of 1638 µmol·g⁻¹·h⁻¹, outperforming 4,8-BT-COF (1046 µmol·g⁻¹·h⁻¹) by about 57%. Structural and photophysical analyses reveal that this pronounced performance difference stems from the critical influence of molecular topology on charge separation, exciton dissociation, and redox kinetics. Specifically, 2,6-BT-COF facilitates more efficient intramolecular charge transfer and suppresses charge recombination losses compared its 4,8-substituted counterpart. This work not only presents two novel, structurally well-defined COF photocatalysts but also establishes a design principle for optimizing photocatalytic efficiency through precise control of molecular connectivity.</p>