Agriculture in the Global South is innately susceptible to climatic variability and change. In many arid and semi-mountainous regions of the developing world, drought is regularly cited as a significant threat to agricultural systems. The objective of this study is to assess the impacts of climate change on drought and land use and land cover (LULC) change in a semi-mountainous region of the Vietnamese Mekong Delta. We assessed previous drought trends (1980–2020) and future drought in the context of climate change, in accordance with three selected scenarios from the Coupled Model Intercomparison Project Phase 6 global climate models which have recently been released by the Intergovernmental Panel on Climate Change (IPCC) (2021–2060) using the Standardized Precipitation Index (SPI). The change of land use for the period 2010–2020 was then assessed and the associated climatic variability explored. The results show that for the period 1980–2019, SPI 3 responds quickly to changes in precipitation, whereas SPI 9 showed a clear trend of precipitation over time. The first longest duration occurrence of drought for SPI 3, SPI 6, and SPI 9 patterns were respectively 15–16, 21, and 25 months at Chau Doc station, and respectively 11, 14–15, and 16–17 months at Tri Ton station. Future precipitation and both maximum/minimum temperatures are projected to increase in both the wet and dry seasons. In addition, for all-time series scales and climate change scenarios, the levels of drought were slight, followed by moderate. In the future, the humidity at Chau Doc station is expected to decrease, while the occurrence of drought events is expected to increase at Tri Ton station, particularly in SPI 6 patterns (110 drought events in 1980–2020, and up to 198 drought events in the future). Moreover, between 2010–2020, the agricultural land area was seen to decrease, replaced by non-agricultural land uses that were found to increase by 22.4%. Among the agricultural land area, forestry, rice crops, and upland rice were found to reduce by 7.5, 16.0, and 21.2%, respectively, while cash crops and perennial crops increased by 26.4% and 170.6%, respectively. Amongst other factors, it is concluded that the variability of climate has led to drought and thus impacted on the conversion of LULC in the study area. Due to low economic efficiency, changing climate conditions, and a lack of irrigated water, the area of rice crops, forestry, aquaculture, and upland rice decreased, replaced by land for orchards for fruit production and other cash crops.