Flotation performance can significantly be affected by seasonal variations due to the changes in water temperature and pulp temperature, type and concentration of dissolved ions in process water. Extreme temperature conditions could be the major factor affecting flotation performance and mask the influence of water chemistry. Therefore, the interactive effects of the temperature and water chemistry should be taken into consideration, particularly for mine sites experiencing extreme temperature conditions. In this paper, effects of temperature, sulphate (SO42−), thiosulphate (S2O32−) and calcium (Ca2+) ions on the flotation performance of a Cu-Pb-Zn complex sulfide ore were investigated using a statistical experimental design and modelling approach. The results were evaluated using ANOVA and regression analysis to determine the significant parameters and derive individual regression models for each flotation response using Design Expert software version 6.0.8. Individual regression models were developed for mass pull, water recovery, grade and recovery of the sulfide minerals using the statistically significant main effects and their interactions. The models were used to determine the concentration of the dissolved ions and pulp temperature required to achieve the maximum zinc recovery, maximum zinc grade or the optimum zinc grade and recovery. The results showed that the water chemistry (i.e., the concentrations of Ca2+, SO42− and S2O32−) affected the flotation performance significantly at low temperature (25 °C). At high pulp temperature (60 °C), however, the temperature was the dominant parameter and masked the effects of water chemistry. Details of the statistical experimental design, discussions of the effects of experimental factors and their interactions on flotation performance, and the development of regression models are presented in this paper.