Abstract: The low-permeability strata are characterized by poor permeability and difficulty in substance transport. The traditional in-situ chemical oxidation (ISCO) techniques often fall short in addressing these challenges. Hydraulic fracturing creates advantageous flow channels, enhancing the ranges 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 strata with a single fracture. It reveals the migration and transformation mechanisms of oxidants across pore-fracture multiscale structures, investigating the influences of injection pressure, oxidant quenching, non-equilibrium adsorption of contaminants, matrix permeability, diffusion coefficients and pollutant distribution on remediation efficiency. The results indicate that the 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. Placing fractures in the lower layer of the contaminant plume is suggested, maintaining hydraulic head post-oxidant injection for optimal remediation. Finally, comparisons of radial and vertical ranges of oxidants between with and without considering reaction conditions are made, proposing the corresponding design strategies to refine synergistic hydraulic fracturing-enhanced remediation technologies based on the theoretical foundations.