Geogenic arsenic (As) contaminated groundwater poses a threat to drinking water safety and ecological health. Dissolved organic matter (DOM) plays a crucial role in As mobilization in Quaternary groundwater systems. Significant spatial variations in As concentrations in groundwater inside and outside the oxbow lakes were observed, but the controlling mechanisms remains unknown. In this study, carbon stable isotopes and fluorescence excitation-emission matrices (EEMs) combined with parallel factor analysis (PARAFAC) were used to elucidate the influence of DOM on contrasting occurrence of As in both inside and outside groundwater of the oxbow lakes along the middle reaches of the Yangtze River. The results showed that groundwater As concentrations outside the oxbow lakes (0.37–485 μg/L) were significantly higher than those in the groundwater inside (0.75–204 μg/L). Stable carbon isotopes suggest that methanogenesis promotes the reductive dissolution of As-bearing Fe(III) oxides/hydroxides, which is the primary process responsible for As enrichment in groundwater outside of oxbow lakes. In contrast, microbial fermentation dominated As mobilization in the groundwater inside of the oxbow lakes. The DOM in the groundwater outside of the oxbow lakes is characterized by a more reductive, predominantly more highly humified and less biologically active humus, while DOM in the groundwater inside consists mainly of microbial humic-like components that is less humified but more biologically active. This study provides new insight to decipher the controlling mechanism of As mobilization in the alluvial-lacustrine aquifers around typical oxbow lakes and is applicable to similar geogenic As-affected floodplain aquifer systems.