The synergistic effect of bimetallic or trimetallic oxide catalysts plays a vital role in sulfate radical-based advanced oxidation processes (SR-AOPs). Herein, a composite catalyst of iron-manganese-copper hollow spheres (FCMHS) was synthesized by hard template method and used for peroxymonosulfate (PMS) activation to degrade sulfamethoxazole (SMX). The catalytic activity of FCMHS was comprehensively evaluated under different conditions (including catalyst loading, PMS dosage, pH etc.). A removal efficiency of 99.1% and a mineralization efficiency of 39.7% for SMX were achieved under the optimal conditions. The kinetic studies demonstrated that the reaction rate for SMX removal by using FCMHS was about 3.5 times faster than that for using copper-manganese hollow spheres (CMHS). The enhanced catalytic performance mainly stemmed from the confined high instantaneous concentration of SMX in the local void space and the synergistic effects of Mn2+/Mn3+/Mn4+, Cu+/Cu2+/Cu3+ and Fe2+/Fe3+ redox cycles to generate radicals and non-radicals. More importantly, the introduction of iron oxide into CMHS substantially facilitated charge transfer at the interface between FCMHS and reaction solution, leading to a high rate and good product selectivity. Furthermore, SMX degradation pathways were proposed by LCMS-IT-TOF assisted with density functional theory (DFT) calculations, and the mechanism was proposed comprehensively. This study opens a reliable and promising avenue for the efficient treatment of antibiotics-polluted water based on trimetallic oxide catalysts.