The analysis of precipitation, snow cover, and temperature based on measured data is important for many applications in hydrology, meteorology, climatology, disaster management, and human activities. In this study, we used long-term historical datasets from the Varzob River Basin (VRB) in Tajikistan to evaluate the trend and magnitudinal changes in temperature, precipitation, and snow cover area in the Anzob (upstream), Maykhura (midstream), and Hushyori (downstream) regions of the VRB using the original Mann–Kendall test, modified Mann–Kendall test, Sen’s slope test, and Pettitt test. The results revealed a decreasing trend in the mean monthly air temperature at Anzob station in the upstream region for all months except January, February, and December between 1960 and 2018 and 1991 to 2018. In each of the three regions, the mean annual temperature indicated a clear upward trend. Seasonal precipitation indicated a large increasing trend in January and February at the Anzob station from 1960 to 2018, but a significant downward trend in April in the upstream, midstream, and downstream regions between 1960 and 1990 and from 1991 to and 2018. In the VRB, almost all stations exhibited a downward trend in annual precipitation across all periods, whereas the upstream region showed a non-significant upward trend between 1960 and 1990. The monthly analysis of snow cover in the VRB based on ground data showed that the maximum increase in snow cover occurs in April at the Anzob station (178 cm) and in March at Maykhura (138 cm) and Hushyori stations (54 cm). The Mann–Kendall test, based on MODIS data, revealed that the monthly snow cover in the VRB increased in April and July while a decrease was recorded in February, September, November, and December from 2001 to 2022. The trend’s stable pattern was observed in March, May, August, and October.