Nitrogen and phosphorus excessive enrichment are major causes of water eutrophication, and variations in nutrients enrichment are strongly influenced by human activities. In this study, annual average water quality from 2001 to 2018 was used to explore the spatiotemporal variations in total nitrogen (TN) and total phosphorus (TP) and their relationships with human activities. Spatially, TN and TP concentrations exhibited significant variations across the five sub-lake zones, and their values were relatively higher in the NW lake zone than the other sub-lake zones. Temporally, TN concentration exhibited weak correlations with years in the NW (R2 = 0.37, p < 0.05) and NE (R2 = 0.43, p < 0.05) lake zones and significant and positive correlations with years in the SW (R2 = 0.62, p < 0.05), SE (R2 = 0.79, p < 0.05), and C (R2 = 0.84, p < 0.05) lake zones. TP concentration exhibited decreasing trends in all lake zones except the NW lake zone (R2 = 0.37, p < 0.05), its value shows a relatively low level and is the restrictive factor to algal growth. The trophic state of the Lake Qiandaohu was determined as mesotrophic. Gross domestic product (GDP) and construction land exhibited strong correlations with TN and TP. Moreover, agriculture nonpoint source pollution was the largest contributor to the excessive enrichment of TN and TP, resulting in water eutrophication. In addition, aquaculture was another major source of nutrients starting in 1999. Although the managers of Lake Qiandaohu implemented a protection-oriented fishery policy, good results cannot be easily achieved with a unilateral policy concerning environmental protection. Thus, comprehensive policies may be more effective than unilateral policies.