Addressing the challenges of uranium extraction from seawater (UES) requires innovative strategies to overcome ultralow concentration (3.3 ppb) and thermodynamic limits. Herein, we propose a regioisomeric engineering strategy to design vinylene-linked covalent organic frameworks (COFs) for synergistic adsorption-photocatalytic UES. Two isomeric COFs, β-PTTN-AO and α-PNNB-AO, were synthesized by tuning the substitution positions of amidoxime (AO) groups on olefin bonds. The β-PTTN-AO isomer achieves a remarkable UES capacity of 12.74 ± 0.21 mg·g⁻¹ in nature seawater, surpassing its α-positioned counterpart (8.9 ± 0.18 mg·g⁻¹) and outperforming most reported photocatalysts. Combined experiments and density functional theory (DFT) theoretical studies correlate regioisomeric configurations with electronic structure modulation and photocatalytic activity. Specifically, β-PTTN-AO enhance π-electron delocalization and strengthen built-in electric fields, promoting exciton dissociation, charge separation, and uranium reduction. This work establishes a molecular design paradigm for COF photocatalysts, advancing sustainable nuclear energy through structural isomerism.