Riparian zones, which are critical interfaces between terrestrial and aquatic ecosystems, are essential for biodiversity, water quality, and landscape stability but are increasingly threatened by anthropogenic activities. The Yangtze River is the longest river in Asia, the riparian zones of which are highly affected by humans, however, they are less studied in terms of pollution change and distribution, which hinders efficient eco-environmental management. This study explored land use and nitrogen and phosphorus non-point source pollution variations in the middle and lower Yangtze River riparian zones from 1995 to 2015 and identified critical risky segments as management priorities. The results revealed great human interventions: Agricultural and constructed lands accounted for 55.2% and 10.2% of the riparian zones, respectively, in 2015, whereas wetlands declined by 2.5% per decade. Using a modified export coefficient model considering terrestrial, climatic, and socioeconomic variations, we found that the nitrogen and phosphorus loads from the riparian zones exhibited a general decline over the two decades, but increased in certain segments due to urbanization. Approximately 10% of the segments contributed over 40% of the nutrient loads. In addition, some river segments with high nutrient loads coincided with ecologically sensitive zones with higher water-quality requirements. Hence, we identified critical riparian zones with higher pollution reduction requirements and management priorities, primarily in the middle reaches of the Yangtze River. This study integrates pollution-load mapping with water-quality target consideration, guiding resource allocation for pollution-control measures, and thus promoting the sustainable management of a key eco-environmental system in Asia.