Antibiotics have become common pollutants in the environment. In most cases, the antibiotics in the environment exist as mixtures, posing joint effects on the organisms. Therefore, the mixture toxicity of the antibiotics can better reflect their environmental risks. In this paper, three types of commonly used antibiotics, i.e., sulfonamides (SAs), SA potentiators (SAPs) and tetracyclines (TCs) were investigated for their binary and tertiary mixture toxicity on three bacteria, Escherichia coli (E. coli), Vibrio fischeri (V. fischeri) and Bacillus subtilis (B.subtilis). It was found that SA-SAP mixtures and SA-SAP-TC mixtures presented synergetic effects on the three bacteria, while SA-TC and SAP-TC mixtures showed antagonistic effects. QSAR investigation suggested that the actual concentration ratio of the components in a mixture could vary a lot from the designed concentration ratio; moreover, the TCs in the ternary mixtures altered the toxic ratio of SAs and SAPs, which lead to the varying joint effects of the ternary mixtures on different bacteria. The present research proposes a novel idea for the mechanistic study of the mixture toxicity, both theoretically and methodologically; and the QSAR studies provide a reference for the prediction of the mixture toxicity, which could be helpful to the risk assessment on joint exposure to antibiotic mixtures.