In the aim of understanding the migration rules of characteristic pollutants in the Erhai Lake, a 3D mathematical model of water quality of Erhai Lake was established using the environmental fluid dynamics model EFDC, and was calibrated and verified by the hydrology and water quality monitoring data of 2015 and 2016. The model was employed to simulate the temporal and spatial variations of TN and TP in the Erhai Lake region in different water periods or with different incoming concentrations. Results reveal that the distributions of TN and TP in different water periods and with different incoming concentrations are similar: the concentrations of TN and TP in the lake area in wet season are generally higher than those in flat and dry seasons; the concentrations of TN and TP under high incoming concentration is higher than those under medium and low incoming concentrations. The average concentrations of TN and TP in the Erhai Lake area in different water periods differ slightly with those under different incoming concentrations, about 0.50 and 0.03 mg/L, respectively. In terms of spatial distribution, the concentrations of TN and TP in the north part of Erhai Lake area are relatively high, and the concentrations of TN and TP in coastal areas and lake bays are higher than those in the lake area. The research results offer reference for the protection and management of Erhai Lake.