While the widely used beta-lactam antibiotics, such as cephalosporins, are known to be susceptible to oxidation by sulfate radical (SO4-center dot), comprehensive study about SO4-center dot -induced oxidation of cephalosporins is still limited, such as the impact of water matrices, and the structure and antibacterial activity of transformation products. Herein, the oxidation of cefalexin (CFX), a most frequently detected cephalosporin, was systematically investigated by thermally activated persulfate (PS). CFX oxidation followed pseudo-first-order kinetics, and SO4-center dot dominantly contributed to the overall oxidation of CFX. The impact of water matrices, such as Cl-, HCO3- and natural organic matter, on CFX degradation was predicted using a pseudo-steady-state kinetic model. The secondary reactive species, such as chlorine and carbonate radicals, were found to contribute to CFX degradation. Product analysis indicated oxidation of CFX to six products (molecular weight of 363), with two stereoisomeric sulfoxides as the primary oxidation products. It was thus suggested that the primary amine on the side chain, and the thioether sulfur and double bond on the six-membered ring were the reactive sites of CFX towards SO4-center dot oxidation. Antibacterial activity assessment showed that the biological activity of CFX solution was significantly diminished after treatment by the thermally activated PS.