The Zuo River originates in northern Vietnam and subsequently flows into China, making it one of the few transboundary rivers that enter Chinese territory. With the ongoing implementation of the “Two Corridors and One Economic Circle” initiative, the Zuo River is poised to serve as a critical conduit for cross-border resource cooperation between China and Vietnam. Nevertheless, foundational research on hydrology and water resources at the full-basin scale remains insufficient. Based on meteorological, hydrological, and water resources data from both China and Vietnam, this study employs the Mann-Kendall (M-K) trend test, wavelet analysis, and the water stress indicator method to investigate the temporal and spatial characteristics of meteorological, hydrological, and water resources variability across the entire Zuo River Basin. The results reveal that precipitation exhibited a distinct spatial distribution pattern, characterized by higher rainfall in the upper reaches and a decreasing gradient in precipitation from south to north. Both precipitation and runoff demonstrated significant intra-annual unevenness and substantial inter-annual variability. From 1965 to 2020, annual precipitation and runoff showed an insignificant decreasing trend, whereas both annual and seasonal air temperature exhibited a significant upward trend. The dominant periodicities for temperature, precipitation, and runoff were identified as 8, 21, and 9 years, respectively. The total volume of renewable water resources in the basin was estimated to be 21.79 billion m3, with an overall water stress index of 0.15, indicating moderate water stress. Due to pronounced inter-annual and intra-annual variability in runoff, water stress was prominent during dry years and dry seasons, which will continue to increase in the future.