The Vietnamese Mekong Delta (VMD) is highly vulnerable to drought, particularly in the context of climate change. Prolonged drought during the dry season has emerged as a significant natural disaster, severely affecting agriculture and socioeconomic development in the region. To enhance water resource management and agricultural productivity, this study examines the characteristics of meteorological droughts using the Standardized Precipitation Index (SPI) and the Standardized Precipitation Evapotranspiration Index (SPEI) in the upper Mekong Delta of Vietnam. The Mann–Kendall (MK) test and Sen’s slope were employed to assess trends in drought and hydrological conditions. The results reveal no significant trends in rainfall, while average temperatures have increased significantly in most months, especially during the dry season. Although water levels and discharge at the Tan Chau and Chau Doc stations have decreased, significant reductions were primarily observed at Chau Doc station from 2000 to 2021. These findings provide critical insights for sustainable water resource management and planning in the VMD, considering future climate variability and changes in hydrological regimes.