This work describes an innovative catalytic process for aqueous trimethoprim degradation, using a fixed-bed continuous flow reactor packed with a manganese(III) meso-substituted porphyrin covalently immobilized functionalized aminopropyl silica gel as the catalyst and H2O2 as a green oxidant. It exhibits remarkable activity and stability, maintaining its performance over extended periods (up to 8 hours) and achieving significant reductions in total organic carbon (TOC = 80%). Importantly, microbiological assays confirmed that this degradation process effectively converts trimethoprim into non-resistance-inducing products.