In this study, the applicability of three gridded datasets was evaluated (Climatic Research Unit (CRU) Time Series (TS) 3.1, “Asian Precipitation—Highly Resolved Observational Data Integration Toward the Evaluation of Water Resources” (APHRODITE)_V1101, and the climate forecast system reanalysis dataset (CFSR)) in different combinations against observational data for predicting the hydrology of the Upper Vakhsh River Basin (UVRB) in Central Asia. Water balance components were computed, the results calibrated with the SUFI-2 approach using the calibration of soil and water assessment tool models (SWAT–CUP) program, and the performance of the model was evaluated. Streamflow simulation using the SWAT model in the UVRB was more sensitive to five parameters (ALPHA_BF, SOL_BD, CN2, CH_K2, and RCHRG_DP). The simulation for calibration, validation, and overall scales showed an acceptable correlation between the observed and simulated monthly streamflow for all combination datasets. The coefficient of determination (R2
) and Nash–Sutcliffe efficiency (NSE) showed “excellent” and “good” values for all datasets. Based on the R2
and NSE from the “excellent” down to “good” datasets, the values were 0.91 and 0.92 using the observational datasets, CRU TS3.1 (0.90 and 0.90), APHRODITE_V1101+CRU TS3.1 (0.74 and 0.76), APHRODITE_V1101+CFSR (0.72 and 0.78), and CFSR (0.67 and 0.74) for the overall scale (1982–2006). The mean annual evapotranspiration values from the UVRB were about 9.93% (APHRODITE_V1101+CFSR), 25.52% (APHRODITE_V1101+CRU TS3.1), 2.9% (CFSR), 21.08% (CRU TS3.1), and 27.28% (observational datasets) of annual precipitation (186.3 mm, 315.7 mm, 72.1 mm, 256.4 mm, and 299.7 mm, out of 1875.9 mm, 1236.9 mm, 2479 mm, 1215.9 mm, and 1098.5 mm). The contributions of the snowmelt to annual runoff were about 81.06% (APHRODITE_V1101+CFSR), 63.12% (APHRODITE_V1101+CRU TS3.1), 82.79% (CFSR), 81.66% (CRU TS3.1), and 67.67% (observational datasets), and the contributions of rain to the annual flow were about 18.94%, 36.88%, 17.21%, 18.34%, and 32.33%, respectively, for the overall scale. We found that gridded climate datasets can be used as an alternative source for hydrological modeling in the Upper Vakhsh River Basin in Central Asia, especially in scarce-observation regions. Water balance components, simulated by the SWAT model, provided a baseline understanding of the hydrological processes through which water management issues can be dealt with in the basin.