All sorts of chemicals get degraded under various environmental stresses, and the degradates coexist with the parent compounds as mixtures in the environment. Antibiotics emerge as an additional concern due to the bioactive nature of both the parent compound and degradation products and their combined exposure to the environment. Therefore, environmental risk assessment of antibiotics and their degradation products is very much necessary. In this direction, we made use of in silico new approach methodologies (NAMs) and machine-learning algorithms. In this study, we have developed a robust and predictive mixture-quantitative structure–activity relationship (QSAR) model with promising quality and predictability (internal: MAE_Train = 0.085, Q_LOO² = 0.849, external: MAE_Test = 0.090, and Q_F1² = 0.859) for predicting the toxicity of the mixtures of a class of antibiotics and their degradation products. To obtain the predictive model, toxicity data of 78 binary fluoroquinolone mixtures in E. coli (endpoint: log 1/IC50 in molar) have been utilized. We have used only 0D–2D descriptors to efficiently encode the structural features of mixture components without any additional complexities. The optimization of the class of mixture descriptors has been performed in this study by using three different mixing rules (linear combination of molecular contributions, the squared molecular contributions, and the norm of molecular contributions). Different machine-learning approaches namely, random forest (RF), ada boost, gradient boost (GB), extreme gradient boost (XGB), support vector machine (SVM), linear support vector machine (LSVM), and ridge regression (RR) have been employed here apart from the conventional partial least squares (PLS) regression to optimize the modeling approach. A rigorous validation protocol has been used for assessing the goodness-of-fit, robustness, and external predictability of the models. Finally, the toxicity of possible untested mixtures of different photodegradation products of fluoroquinolones has been predicted using the best model reported in this study.