The transfer of advanced oxidation processes (AOPs) to real-world applications faces several technology challenges involving oxidation performance, catalyst cost, poor reactive oxygen species (ROS) yield, and long-term stability. This work aims to develop a reactive, efficient, and stable MXene-based nanocatalyst, namely Fe3O4@Ti3C2Tx, for ultrafast removal of the selected sulfonamide antibiotics. As revealed by extensive nanocatalyst characterization, the MXene surface not only anchors Fe/Fe3O4 nanoparticles (NPs) but also prevents NP agglomeration. Notably, the conductive interface between MXene and Fe3O4 promotes the Fe(II)/Fe(III) redox cycle and accelerates peroxymonosulfate (PMS) activation. The Fe3O4@Ti3C2Tx demonstrates excellent catalytic activity by achieving complete sulfamethoxazole (SMX) degradation within 6 min and maintained its catalytic activity after 5 continuous cycles. In the Fe3O4@Ti3C2Tx/PMS system, multiple ROS (e.g., •OH, SO4•-, O2•-) are involved but 1O2 was found to be the primary ROS for SMX degradation. The presence of co-exiting inorganic impurities and pH changes may hinder SMX degradation. Finally, elucidating possible degradation pathways of SMX would greatly aid in treating antibiotic-containing wastewater.