Snow cover has a key role in balancing the Earth’s surface temperature and can help in filling rivers and reservoirs. In this study, 8-day MOD10A2 images are employed to monitor the spatiotemporal changes in snow cover in the Sefid-Rud basin and its eleven sub-basins during 2000–2019. The non-parametric Mann–Kendall (MK) test and its associated Sen’s slope estimator are utilized to estimate the trends in annual, seasonal, and monthly snow cover changes. The Sen’s slope results show a decrease in the snow cover for the basin, statistically significant toward the central and southern parts of the basin. In the winter season, a decreasing trend is observed, where its decreasing rate is higher than the annual rate. The trends in the calendar months are like the seasons, i.e., December, January, and February exhibit a decreasing trend, like the winter season. The Goltapeh-Zarinabad and Ghorveh-Dehgolan sub-basins show decreasing snow cover rates of −0.51 and −0.68 (%/year) during 2000–2019, respectively, the only two sub-basins whose gradients are statistically significant at the 95% confidence level. The Pearson correlation analysis between elevation and snow cover for each year shows that the highest and lowest correlations are 0.81 for 2007 and 0.59 for 2017. Finally, analysis of the MCD12Q1 land cover data shows that a significant portion of non-vegetated lands have turned into grasslands, mainly in the central part of the basin, where the significant gradual snow cover decline is observed. The results can guide stakeholders and policymakers in the development of a sustainable environment in the face of climate change.