The upper Unstrut River is located in Germany at the modern Central European climate boundary of Cfb and Dfb climate. The river drains a loess landscape, which has experienced important environmental changes throughout the last 12,000 years. To evaluate the impacts of these changes on floodplain evolution, a multi-proxy research program, consisting of 2D electrical resistivity tomography profiling (ERT), vibracoring, and sedimentological investigations, 14C and OSL dating were applied. From base to top the investigations the following fluvial deposits were revealed: (1) gravels embedded in a fine-grained sediment matrix (interpreted as fluvial bedload deposits); (2) silty sediment with pedogenic features (interpreted as overbank floodplain deposits); (3) peat and tufa deposits (interpreted as wetland deposits) intercalated by pedogenetically influenced silty sediments (interpreted as overbank deposits); (4) humic silty sediment with some pedogenic features (interpreted as overbank floodplain deposits); and (5) silty sediments (interpreted as overbank deposits). Radiocarbon and luminescence dates yielded the following periods for sediment formation: (1) Younger Dryas to Preboreal period (around 11.6 cal ka BP); (2) Preboreal to early Atlantic period (approx. 11.6 to 7.0 cal ka BP); (3) early Atlantic to late Subboreal period (approx. 7.3 to 3.4 cal ka BP); (4) late Subboreal to early Subatlantic period (2.9 to 2.3 cal ka BP); and (5) late Subatlantic period (approx. 1.0 to 0.6 cal ka BP). The results suggest that floodplain development during the latest Pleistocene and early Holocene (approx. 11.6 to 7.0 cal ka BP) was considerably controlled by climatic conditions and short-term climate variabilities, which caused gravel deposition and overbank sedimentation. Afterwards floodplain conditions varied between rather stable (peat and tufa development, initial soil formation) and active periods (deposition of overbank fines). In this context, active periods with increased sediment input prevailed from approx. 5.1 to 3.4 cal ka BP, 2.9 to 2.3 cal ka, and 1.0 to 0.6 cal ka BP, temporally corresponding well with increased land-use phases of the past. In conclusion this study demonstrates that the investigated Unstrut catchment has reacted very sensitively to natural and human-induced changes during the latest Pleistocene and Holocene. Consequently, this high vulnerability to external changes should be considered in future river predictions or river management.