Mangroves are one of the most valuable and productive coastal ecosystems. Previous studies show a severe loss of mangroves around the world over the last several decades due to natural and anthropogenic activities. Mangroves located in the southeastern part of the Mekong River Delta (MRD) are also affected by these activities. Shrimp farming is considered as one of the main drivers causing the rapid loss and degradation of mangroves. The goal of this study is to assess the spatiotemporal changes in land use and distribution of mangroves in the Soc Trang and Bac Lieu provinces of the southeastern part of the MRD. Multi-temporal Landsat data were used for land use and land cover (LULC) classification using the maximum-likelihood classification algorithm. The changes in mangrove forest areas were monitored using medium spatial resolution (Landsat-5 Thematic Mapper and Landsat-8 Operational Land Imager) satellite imageries from 1988 to 2018. In the study area, there were seven major LULC types namely, dense mangroves, sparse mangroves, aquaculture farms, arable land with crop cover, arable land without crop cover, settlements, and water bodies. The overall accuracies of the LULC maps in 1988, 1998, 2008, and 2018 were 81.2%, 83.3%, 78.3%, and 81.9%, respectively. This study reveals that dense and sparse mangrove forests have decreased by 90% from 5495 hectares (ha) to 515 ha and by 55% from 14,105 to 6289 ha, respectively from 1988 to 2018. On the other hand, the aquaculture farm has increased at the rate of 5024 ha/year for a period of 30 years. This rapid growth of aquaculture farming activities caused the rapid loss and degradation of mangroves in the MRD. Quantitative information about mangrove change obtained by this study is considered to be useful for future coastal management and relevant policies in the MRD.