The synergistic effect of photocatalysis on pyrite (FeS2) Fenton process largely depends on its morphology. However, the relationship between morphology and performance remains unclear. The study aims to investigate how different morphologies FeS2 (cube, octahedron and sphere) affects the photo-Fenton degradation of sulfadiazine (SDZ) by considering crystal planes exposure and sulfur (S) vacancy. Results demonstrated octahedral FeS2 exhibited highest efficiency in photo-Fenton degradation (93.4 %) and mineralization (82.3 %) of SDZ. The synergistic effect of photocatalysis on Fenton process of octahedral FeS2 was particularly notable. The unique characteristics of octahedral morphology accelerated the Fe3+ to Fe2+ cycle and various active species generation (·OH, h+, ·O2– and ·SO4-). Specifically, the exposed crystal planes and S vacancies was the key reason influencing the photocatalytic synergy of FeS2. The octahedron with exposed crystal planes (200) exhibited strongest crystallographic energies, larger specific surface area with sharp corners and edges. These features improved adsorption performance and increased the release of Fe2+. Furthermore, the crystal planes narrowed the band gap of octahedral FeS2, facilitating the generation of more photo-generated carriers. The higher concentrations of S vacancies on octahedral FeS2 provided more active sites, reducing the band gap, and extending the carrier lifetime. Given the increasing demand for practical applications of the FeS2 photo-Fenton in pollutant treatment, this study establishes a solid theoretical foundation for the design and optimization of high-efficiency and low-cost catalysts.