This study investigated the policy instruments to key tasks required to deal with industrial and technological innovation issues and establish a regional innovation system in the Mekong Delta region in order to find countermeasures by injecting scientific and technological factors to solve the current problems of the region. First, we conducted the research with regard to the status and environment of the region. Second, a field visiting survey was implemented to analyze the results of international efforts and regional capacity to solve the problems attendant upon introducing technologies related to the Fourth Industrial Revolution. Third, we derived the key policy issues and challenges from the results of field visiting survey and experts' conference with a deep focus on technological transfer and international cooperation to enhance the capability in science and technology field. Fourth, we conducted the opinion survey of the experts from Korea and Vietnam, to converge local opinions from both countries and analyzed the results. Sixth, We were transform the RIS Framework by a basic model of Cooke & Memedovic (2006). The range of research subjects is responding to climate change, managing water resources, coordinating energy and industrial structure, making a resilient Mekong regional ecosystem, smartification of local cities, and improving life quality of citizens, and so on. The results of this study are expected to be the beginning of fundamental research in the mid to long-term view of the Mekong Delta region innovation system of Korea and Vietnam and to evaluate the master plan.