Antibiotics may be exposed in a mixed state in natural environments. The toxicity of antibiotic mixtures exhibits time-dependent characteristics, and data on the time-dependent toxicity of antibiotic mixtures is also relatively lacking. In this study, the toxicities of 45 binary mixtures composed of five antibiotics were investigated against Vibrio qinghaiensis sp.-Q67 (Q67) at multiple exposure times (4, 6, 8, 10, and 12 h). Quantitative structure−activity relationship (QSAR) models were developed for predicting the time-dependent toxicities of 45 binary mixtures. The results showed that the best QSAR models presented coefficient of determination (R 2 ) of (0.818−0.913) and explained variance in prediction leave-one-out (Q 2 LOO ) of (0.781−0.894) and predictive ability (Q 2 F1 , Q 2 F2 , Q 2 F3 > 0.682, concordance correlation coefficient > 0.859). The R 2 values of QSAR models outperformed the R 2 (0.628−0.810) of the conventional concentration addition models and the R 2 (0.654−0.792) of the independent action models. Furthermore, the QSAR models showed higher R 2 and Q 2 LOO values at 4 h compared to other exposure times. Specifically, the model at the 30% effective concentration (EC 30 ) had R 2 of 0.902 and Q 2 LOO of 0.883, while the model at the 50% effective concentration (EC 50 ) had R 2 of 0.913 and Q 2 LOO of 0.894. The CATS2D_04_DP descriptor was found to be the most dominant and negatively correlated factor influencing the toxicity of mixed antibiotics against Q67 in the nine QSAR models developed over five exposure times. The reduction in the number of DP pharmacophore point pairs with a topological distance of 4 in the represented molecules is the primary cause for the rise in the time-dependent toxicity of the antibiotics against Q67.