Cefotaxime (CTX), cephalexin (CFX), cephradine (CFD), cephapirin (CFP), and cefazolin (CFZ) were selected as target cephalosporin antibiotics to study their oxidative transformation by δ-MnO2. Although they all have the same core structure (7-aminodesacetoxycephalosporanic acid), very different MnO2 oxidation rates were observed at pH 4 (the initial reaction rate constant kinit ranged from 0.014 to 2.6 h-1). An extensive investigation of the substructure compounds and byproduct analysis revealed that the oxidation mainly occurred at the following two sites on the core structure: (1) the sulfur atom in the cephem ring and (2) the carbon-carbon double bond (C═C) and its proximal carboxylic acid group. In the case of (2), when there is an acetyloxymethyl group at the C-3 position of the core structure, the formation of the keto-sulfone byproducts was inhibited. The overall results indicated that a substituent at the C-3 position could stabilize the core structure, which would result in a decrease in the oxidation rate; however, a substituent at the amine position of the core structure might affect the overall degradation rate of the cephalosporin, depending on its reactivity with MnO2. Thus, the apparent reaction rates varied widely in the trend of CTX > CFP > CFD > core structure ≈ CFX > CFZ. The mechanistic elucidation can also help explain the degradation rates of cephalosporin antibiotics in other oxidation processes.