A proof-of-concept MODFLOW 6 groundwater model was developed to represent the bedrock, delta, and alluvially-deposited aquifers underlying the Mekong River Basin approximately between Phnom Penh, Cambodia and Cao Lanh, Vietnam. The model was constructed using square grid cells measuring 2,200 meters on each side. The proof-of-concept groundwater model was used to simulate environmental baseline conditions, representative of a 20-year period with stresses from November 1990 through October 2010. Additionally, a 20-year period of drier conditions with sea-level rise was also simulated that approximates the Mekong River Commission C3 climate scenario (drier climate with sea level rise; Mekong River Commission, 2019). The end of the baseline scenario was assumed to approximate current (2020) groundwater conditions in the model area without groundwater pumping. The models each include a steady-state period that calculates initial conditions for the 20-year transient period in each scenario followed by 80 quarterly stress periods that are each three months long. The dry season, which occurs annually between November and April of the following year, and wet season, which occurs annually between May and October, were each represented using two model stress periods. Relative water level differences were calculated for equivalent stress periods between the baseline and dry condition models. Relative water level differences are presented in this data release for the end of the last dry season (stress period 79) and the last wet season (stress period 81). The proof-of-concept MODFLOW 6 groundwater model (Langevin and others, 2017) was constructed to provide a basis for linking a groundwater model and socioeconomic model in the study area and is not intended to be used to represent localized hydrologic processes or changes in hydrogeology. The proof-of-concept groundwater model is simplified in its representation of subsurface hydrogeology and the hydrologic processes that can influence water levels, streamflow, or groundwater availability in the study area; however, it can be used to show how a system may respond differentially to variations in model inputs, primarily those that represent stresses from changing climate. The hydrogeology and other model inputs can be refined in the future to create an independently robust tool that water managers can use to assess groundwater availability in the study area. The data release directories contain ancillary, bin, georef, model, output, and source folders with the necessary executable and input files for the following models: (1) a combined steady-state and 20-year transient MODFLOW 6 groundwater flow model representative of baseline conditions, and (2) a combined steady-state and 20-year transient MODFLOW 6 groundwater flow model representative of climatically drier conditions with sea-level rise. The dry-climate scenario is an approximation of the Mekong River Commission C3 scenario: drier climate with sea-level rise. This USGS data release contains all of the input and output files for the model described in the associated journal article (https://doi.org/10.1111/plos.xxx?). REFERENCE: Mekong River Commission. Interactive report for the Council Study: Findings and Recommendations. Vientiane, Lao PDR: Mekong River Commission Secretariat; 2019 Sep. doi:10.52107/mrc.ajg58l