Antibiotic contamination constitutes a serious environmental and public health risk. In order to fill the gap in the study of plasma degradation of erythromycin (ERY), this paper systematically investigated the mechanism of ERY degradation by dielectric barrier discharge (DBD) plasma. The underlying reaction mechanisms were investigated by experiments and molecular dynamics simulations. Plasma emission spectra revealed active hydroxyl radicals (·OH) and argon (Ar) spectral lines. The degradation efficiency of plasma treatment for ERY was found to be strongly influenced by treatment parameters, including applied voltage, treatment duration, and gas flow rate. In particular, a maximum degradation of 90% was achieved for a 250 mg/L ERY solution under conditions of 18 kV voltage, 850 sccm gas flow rate, and 60 min of treatment. The presence of ·OH and hydrogen peroxide (H