Arsenic contamination in the Mekong River is a well-known environmental issue yet to be resolved due to its transboundary nature which further limits its access and data collection. Other than that, the key mechanisms that controlling the arsenic release in Mekong sub-region groundwater was heterogeneously distributed and can be varied from region to region. The main purpose of this project is to identify the regional arsenic contamination levels in the hope of helping the government integrate regional groundwater arsenic risk reduction policy in their near future planning. Sampling was conducted during May and August 2022 in Cambodia and Laos, respectively. The findings revealed that the topography of certain areas in Cambodia has exposed significantly high concentrations of arsenic in groundwater compared to those in Laos. About 33% of the sampling sites in Cambodia had shown a high arsenic contamination (> 10 µg/L, WHO guideline) with its concentration ranging from 47.7 ± 0.8 to 696.9 ± 5.6 ppb. The physicochemical properties revealed that the arsenic controlling mechanisms were totally different between both study area. More regional and site-specific arsenic contamination research related to climate change and arsenic hydrology at regional levels should be carried out to ensure the water safety plan in specific regions. Further, we believe that the findings of this study will be beneficial to policy and regional water safety plans for the Mekong River, especially in Cambodia.