The Yarlung Tsangpo River is one of the highest major rivers in the world. The river is known for its pristine landscape. However, in recent years, increasing human activities, such as inhabitation, afforestation, and infrastructure projects, have significantly disturbed this fluvial system, while their impacts are not fully known. In this study, the water and sediment transport processes in the Nugesha–Yangcun (N–Y) reach of the Yarlung Tsangpo River, as well as the impact of human activity, are investigated. The N–Y sub-catchment consists of two parts, i.e., the Lhasa River catchment and the mainstream catchment. Riverine discharge, suspended sediment concentration (SSC), and precipitation data are acquired, and a detailed investigation is conducted. The water yield has not changed considerably in recent years, while the sediment yield has exhibited a sharp decline, from ~5 Mt to ~1 Mt. The sediment decrease is mainly caused by the reduced sediment source, which is considered highly related to afforestation. In addition, the dominant sediment contributor has changed from the mainstream catchment to the tributary catchment (while the sediment yield in the mainstream catchment has decreased to almost zero). An anomalously enhanced SSC occurred in the Lhasa River in two consecutive years from 2015, with the SSC value increasing sharply from 0.2 kg/m3 to 0.8 kg/m3, and maintaining a high level for approximately three months. This phenomenon is considered to be related to infrastructure projects in the same period, with the SSC recovered after road construction ended. The increasing human activities have had significant impacts on the sediment regimes in the Yarlung Tsangpo River; hence, more attention should be paid to river basin management.