Water-use efficiency (WUE) is a crucial physiological index in carbon–water interactions and is defined as the ratio of vegetation productivity to water loss. The variation in climatic variables and drought have the most significant effects on WUE and evapotranspiration (ET). Nevertheless, how WUE varies with climate factors and drought processes in the Tianshan Mountains (TMS) is still poorly understood. In the present work, we analyzed the spatiotemporal variations in WUE, and investigated the correlations between WUE, climate factors, and drought, in the study area. The results showed that, in the TMS during 2000–2020, annual net primary productivity (NPP) ranged from 147.9 to 189.4 gC·m⁻², annual ET was in the range of 212.5–285.8 mm, and annual WUE ranged from 0.66 to 0.78 gC·kg⁻¹·H₂O. Both NPP and ET exhibited an increasing trend with some fluctuation, whereas WUE showed the opposite tendency during the study period. The obtained results demonstrated that the decrease in WUE was primarily because of the increase in ET. There were obvious differences in WUE, under different land-use types, caused by NPP and ET. However, the interannual variation in WUE showed small fluctuations and the dynamic process of WUE in each land-use type showed good consistency. Temperature and wind speed had a positive influence on WUE in the middle and eastern regions of the TMS. Precipitation also played a mainly positive role in enhancing WUE, especially on the northern slope of the TMS. There was strong spatial heterogeneity of the correlation coefficient (0.68, p < 0.05) between WUE and the temperature vegetation drought index (TVDI). Moreover, the slopes of WUE and TVDI showed good consistency in terms of spatial distribution, suggesting that drought had a significant impact on ecosystem WUE. This work will enhance the understanding of WUE variation, and provide scientific evidence for water resource management and sustainable utilization in the study area.