In this study, future projections of monthly total precipitation and monthly average temperatures are carried out using 22 global circulation models (GCMs) from phase 6 of the Coupled Model Intercomparison Project (CMIP6) of the Mediterranean region. The Multi-Model Ensembles (MME) are created with GCMs that best estimate observed values with the Artificial Neural Networks (ANN) based statistical downscaling method. The performance of GCMs is evaluated with six different statistical performance criteria. The MMEs are found to be better than used individual GCMs in simulating historical temperature and precipitation in the region. The projections are made for the years 2021–2100 according to the two integrated scenarios of socio-economic development and greenhouse gas emissions (SSP2–4.5, SSP5–8.5). The projections with the MMEs show that decreasing precipitation is calculated as 15% for SSP2–4.5 and 20% for SSP5–8.5. Also, the increase in temperature is found between 1.0 and 2.2 °C and between 1.8 and 3.1 °C for the SSP2–4.5 and SSP5–8.5, respectively. In addition, the possible decrease in precipitation in the coastal part of the region is higher than in other regions. On the other hand, possible temperature increases in the region's high altitudes have been determined more than in the coastal areas.