Combined sewer overflow (CSO) is one of the main causes of contamination in receiving bodies during the rainy period. The objective of this research was to evaluate the behavior of three combined sewage discharges into the Tomebamba River in the city of Cuenca, Ecuador. For this, the registration of 18 CSO events was carried out. The following water quality parameters were analyzed from the field survey (March 2017 to May 2018): conductivity, turbidity, BOD5, COD, fecal and total coliforms, nitrates, nitrites, ammoniacal nitrogen, dissolved orthophosphate and total phosphorus. The results show that CSOs contribute to the deterioration of the water quality of the Tomebamba River during the rainy season. The analysis of the dynamics of the pollutants determined that the maximum conductivity values occur at the beginning of the discharge, and the maximum turbidity is located near the peak discharge flow. The relationship between rain and the characteristics of the CSO was also analyzed through a canonical correlation analysis and partial least squares regression, obtaining a prediction model of pollutants based on the precipitation parameters. These results can be used for the implementation of integrated ecological models that enable a complete analysis of the city’s sanitation systems, their impact on the receiving bodies and their restoration.