This research focused on the characterization of sediment-derived DOM (SDOM) extracted from sediment of Yellow River and the binding behaviors of ceftazidime (CAZ) with the presence of SDOM. The morphology, surface composition and structure of SDOM and the complexation between SDOM and CAZ in terms of component features, binding capacity and sequence were studied by multiple approaches. Results showed that SDOM was in situ autochthonous-dominated with a low weight-average molecular weight and aromaticity. The multiple morphological characteristics, high surface oxygen contents (53.49%) and more aliphatic of SDOM were further confirmed. Studies on SDOM-CAZ interaction suggested that the functional groups and chemical compositions of SDOM were susceptible to CAZ. In more detail, the aromatic protons and aliphatic protons of CAZ impacted significantly and the binding between CAZ and SDOM might relate to noncovalent. The protein-like fractions were considered to primary participant and the aromatics and amides as mainly active sites interaction with CAZ. These findings have significant implications on the environmental fate of cephalosporin antibiotics and that of sediment-derived DOM.