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Groundwater is a precious resource that depends directly by the climate regime. The South East Europe region presents high sensitive climatic parameters due to climate change. Different approaches could be applied to assess the climate change impact on the water resources. Climate models and land cover data were used here in two shift times, present (2011-2040) and future (2041-2070), to evaluate the climate effect on groundwater resources. 'New Implemented Spatial-Temporal On Regions-Climate Effect on Groundwater' (NISTOR-CEGW) method was proposed for this study because it implies an analysis at spatial scale based on land cover, actual crop evapotranspiration (AETc), effective precipitation, and De Martonne Aridity Index. This method uses an inference matrix to combine the effective precipitation and De Martonne Aridity Index to assess the impact of climate on groundwater giving six classes of effects, from very low to extremely high. For the present period, the findings indicate extremely high climate effect in the Pannonian basin, in the East and South of Romania, in the North and South of Bulgaria, in the East and central parts of Macedonia, in the North and East of Greece and in the European part of Turkey. In the future, the areas with the extremely high climate effect on groundwater increase mainly in the northern, eastern, and southeastern sides of the South East Europe region. The Dinarics and the Alps Mountains are the areas with low and very low effect of climate on groundwater. These areas experience a very humid and extremely humid climate. The findings show that about half territory of the South East Europe is facing with drought and the environment, groundwater, and related ecosystems are triggered by climate change.