Poyang Lake, the largest freshwater lake and typical river-connected lake in China, was selected as a research area. A method was first proposed to quantitatively explore the mechanisms driving water quality evolution, in which the weights of horizontal boundary input, self-purification, vertical atmospheric deposition and sediment release could be determined. A two-dimensional water environment model for Poyang Lake was developed in the framework of the Finite Volume Method and calibrated against the field investigated data. Four typical months in a common-water year were determined for numerical experiments to investigate the temporal and spatial water quality driving mechanisms in Poyang Lake. The results suggested that boundary input and self-purification have the greatest effect on dominating the water quality in Poyang Lake, followed by atmospheric deposition and sediment release. The driving weights of these four factors are 57.2%, 26.5%, 9.3%, and 7.0%, respectively. However, the impact on lake water quality of external water quality, aquatic ecosystem structure, precipitation distribution, and meteorological conditions, which are attributed to the disparities in geographical situation, varied significantly with seasons and locations.