Large-amplitude meanders may form in low-energy rivers despite generally limited mobility in theses systems. Exceptionally large meanders which even extend beyond the valley sides have developed in the Overijsselse Vecht river (the Netherlands) between ca. 1400 CE (Common Era) and the early 1900s, when channelization occurred. Previous studies have attributed the enhanced lateral dynamics of this river to changes in river regime due to increased discharges, reflecting climate and/or land-use alterations in the catchment. This paper focuses on local aspects that may explain why exceptionally large meanders developed at specific sites. Through an integrated analysis based on archaeological, historical, and geomorphological data along with optically stimulated luminescence dating, we investigated the relative impact of three direct and indirect anthropogenic causes for the local morphological change and enhanced lateral migration rates: (1) lack of strategies to manage fluvial erosion; (2) a strong increase in the number of farmsteads and related intensified local land use from the High Middle Ages onwards; and (3) (human-induced) drift-sand activity directly adjacent to the river bends, causing a change in bank stability. Combined, these factors led locally to meander amplitudes well beyond the valley sides. Lessons learned at this site are relevant for management and restoration of meandering rivers in similar settings elsewhere, particularly in meeting the need to estimate spatial demands of (restored) low-energy fluvial systems and manage bank erosion.