The Mekong River basin (MRB) is a transboundary basin that supports livelihoods of over 70 million inhabitants and diverse terrestrial-aquatic ecosystems. This critical lifeline for people and ecosystems is under transformation due to climatic stressors and human activities (e.g., land use change and dam construction). Thus, there is an urgent need to better understand the changing hydrological and ecological systems in the MRB and develop improved adaptation strategies. This, however, is hampered partly by lack of sufficient, reliable, and accessible observational data across the basin. Here, we fill this long-standing gap for MRB by synthesizing climate, hydrological, ecological, and socioeconomic data from various disparate sources. The data— including groundwater records digitized from the literature—provide crucial insights into surface water systems, groundwater dynamics, land use patterns, and socioeconomic changes. The analyses presented also shed light on uncertainties associated with various datasets and the most appropriate choices. These datasets are expected to advance socio-hydrological research and inform science-based management decisions and policymaking for sustainable food-energy-water, livelihood, and ecological systems in the MRB.