Land use change (LUC) driven by human activities and natural factors has resulted in the global loss of native biodiversity and the alteration of ecological processes and services across different ecosystems. It is thus necessary to analyze the trends and driving factors that influence land use changes. In this study, moderate resolution Landsat images were freely downloaded from the United States Geological Survey (USGS) archives, analyzed using the random forest (RF) algorithm and mapped in ArcGIS 10.2 software to examine the LUC trends from 1990 to 2016 in the Kilombero valley floodplain (KVFP), Tanzania. Participatory rural appraisals (PRA) and household questionnaire surveys were used to assess the potential drivers of LUC. The results show that, from 1990 to 2016, the agricultural land and grassland increased by 11.3% and 13.3%, respectively, while the floodplain wetland area decreased from 4.6% in 1990 to 0.9% in 2016. Based on a questionnaire survey, the intensification of human activities was identified as the proximate driver while population growth, a growing market demand and price incentives for agricultural and forest products coupled with improved infrastructure and biophysical factors such as soil properties, climate variability and terrain characteristics were identified as the underlying drivers of LUC. However, there is interplay among these factors acting simultaneously as well as differently that influence land use changes. Based on these findings, future sustainable land management strategies should include the introduction of the alternative environmentally friendly sources of livelihood, such as beekeeping, the promotion of community participation and education on the importance of sustainable wetland management.