Abstract: Low-permeability strata are characterized by poor permeability and difficulty in substance transport. Traditional In-Situ Chemical Oxidation (ISCO) techniques often fall short in addressing these challenges. Hydraulic fracturing creates advantageous flow channels, enhancing the reach of injected oxidants. However, the current understanding of the synergistic mechanism between fracturing and oxidation remains limited, leading to a lack of corresponding design guidelines. Thus, this study considers compound solute advection, diffusion, reactions, and natural oxidant demand (NOD) to establish a two-dimensional axisymmetric model for ISCO remediation in low-permeability stratum with a single fracture. It reveals the migration and transformation mechanisms of oxidants across pore-fracture multiscale structures, investigating the influence of injection pressure, oxidant quenching, non-equilibrium adsorption of contaminants, matrix permeability, diffusion coefficients, and pollutant distribution on remediation efficiency. Results indicate that hydraulic fracturing ISCO is more suitable for low-permeability contaminated strata with matrix permeability ≤10-7 m/s and diffusion coefficients ≤8.4×10-10 m2/s. It suggests placing fractures in the lower layer of the contaminant plume, maintaining hydraulic head post-oxidant injection for optimal remediation. Finally, comparisons of radial and vertical reach of oxidants between with and without considering reaction conditions are made, proposing corresponding design strategies to refine synergistic hydraulic fracturing-enhanced remediation technologies based on theoretical foundations.