The inability to recycle Fenton reagents and a narrow pH range restricts hematite (Fe2O3) application in the actual photo-Fenton system. The engineering of surface structures is identified as an effective approach for enhancing the photo-Fenton activity of the material. In this work, three different morphologies (nanosheet, cube, and ring) Fe2O3 materials containing oxygen vacancies (OVs) were synthesized by hydrothermal method, and a novel system for the photo-Fenton degradation of sulfamethazine was examined. In the presence of oxalic acid, the Fe2O3/oxalic acid heterogeneous catalytic system demonstrated the in situ generation of H2O2 and facilitated Fenton-like reactions. The as-prepared nanosheet-Fe2O3 showed the highest photo-Fenton degradation efficiency. The free radical capture experiment was investigated by using different free radical sacrificial agents, and the results suggested that superoxide radicals were the principal active species involved. Ecotoxicity assessments utilizing toxicity prediction software assessed the reaction intermediates generated during sulfamethazine degradation via a quantitative structure–activity relationship method, indicating that these intermediates exhibited reduced developmental toxicity. The possible pathways of sulfamethazine degradation and mechanism for synergistic degradation sulfamethazine effect between Fe2O3 and oxalic acid were proposed. This research presents an effective strategy for the design and synthesis of Fe2O3 photocatalysts with various morphologies and oxygen vacancies, suitable for application in photo-Fenton catalysis and related environmental contexts.