In this study we resolve the paleoclimatic variability and its impact onto human history over the Mid-Holocene in the Katarraktes Cave System, Northern Greece. The study area is one of the most important Early Bronze Age archaeological sites of the eastern Mediterranean and comprises a cave and an associate rockshelter, lying on the south flanks of the Krousovitis River canyon. We analyze a clastic sedimentary sequence preserved at the entrance of the Katarraktes Cave by combining sedimentological, mineralogical and geochemical data with magnetic parameter measurements and age constraints. Our results reveal that warm and wet climatic conditions prevail in the area during the Mid-Holocene that were interrupted by short-term cold and dry events. We show that the fluvial response to these climatic variations had a pronounced impact onto human activities, as continuous sedimentation by floodwaters within the cave until ~6600 BP prohibit early settlers from using the sheltered environment. However, high incision rates (~1.5 mm/yr) of the Krousovitis River favored the use of the rockshelter during the Mid- to Late Holocene. Our study demonstrates that the interplay between climate and surface processes was the key factor that controlled human occupation in this important archaeological site.