The Yangtze River Basin is vital to China’s water security and flood management yet lacks a basin-wide quantitative assessment of long-term hydroclimatic changes. This study uses the high-resolution CMFD 2.0 dataset and the VIC model to evaluate spatiotemporal trends in precipitation and natural streamflow from 1951 to 2020. The results show a significant increase in annual precipitation in the upper basin (1.10 mm yr⁻¹, p < 0.05), particularly during the wet season, with spatially concentrated increases along the eastern Tibetan Plateau. The VIC model performed reliably across major stations, with NSE > 0.9 and PBIAS within ±10% during calibration. Natural streamflow trends are spatially heterogeneous: upper mainstream stations (e.g., Shigu, Panzhihua, Zhutuo) exhibit significant increases (6.25–14.58 m³/s per year), while lower stations remain stable or decline. Seasonally, wet-season streamflow increased in the upper basin, whereas dry-season streamflow decreased in the middle and lower reaches. At Yichang, natural simulations reveal growing seasonal extremes, with rising wet-season and declining dry-season flows (−19.06 m³/s yr⁻¹). Human interventions have partially offset these extremes. Since 1990, observed peak discharge at Yichang during the wet season has decreased by 10.04% compared to natural streamflow, while the dry-season minimum discharge has increased by 27.63%. This shows that large reservoirs help reduce flood peaks and increase low flows. These findings highlight the intensifying impacts of climate variability and human regulation on hydrological processes and provide a scientific basis for adaptive water resource management in large river basins.