Abstract: Significant progress has been made in the ecological and environmental management of the Changjiang River Basin. However, the persistent challenges often represent long-standing issues, with thorough remediation posing considerable difficulties. Honghu Lake, a key focus lake in the 14th Five-Year Plan for the protection of the water ecological environment in the Changjiang River Basin, serves as a typical example. To this end, we studied the spatiotemporal characteristics of key water quality indicators in Honghu Lake from 2021 to 2023—namely chlorophyll-a, total phosphorus (TP), total nitrogen (TN), and the permanganate index (COD_Mn)—as well as their interannual trends from 1982 to 2023. Methods such as the quantile approach and the pressure-response relationship were employed to determine the nitrogen and phosphorus reference conditions and appropriate control standards for Honghu Lake. The results indicated that: ① From 2021 to 2023, the water quality of Honghu Lake was predominantly Class Ⅳ to worse than Class Ⅴ. The primary pollutants exceeding standards were TN and TP, followed by COD_Mn. Their average concentrations were 1.72 mg/L, 0.132 mg/L, and 19.6 mg/L, respectively. The frequency with which the lake-wide average chlorophyll-a concentration exceeded 30 μg/L was 30%, and all areas of the lake experienced instances where chlorophyll-a exceeded 100 μg/L, raising concerns over water quality and ecological safety. Since 2016, nitrogen and phosphorus concentrations in Honghu Lake have shown a significant upward trend, indicating a worsening trend in water pollution. ② The inferred reference condition for TP in Honghu Lake was approximately 0.029 mg/L, while the reference condition for TN likely fell within the range of 0.50~1.16 mg/L. Honghu Lake should continue to strengthen water pollution prevention and control, reducing loads of nitrogen, phosphorus, and oxygen-consuming organic pollutants. Furthermore, the control of TN should not be overlooked. ③ Systematic pollution control should focus on key areas such as the upstream regions and the Four Lakes main canal, with priority given to urban and rural domestic sewage, livestock and poultry farming, and agricultural cultivation. Appropriate nitrogen and phosphorus control targets for inflowing rivers should be established from the perspective of the aquatic ecological security of the Four Lake Basins. It is recommended that management targets for TP and TN at key monitoring sections of rivers entering the lake be set at 0.050 mg/L and 1.00 mg/L, respectively.