Contaminant loads to rivers of the Canadian oil sands region are linked to industrial and natural sources. To date, biomonitoring studies have been unable to unequivocally assess potential environmental impacts associated with this development. As part of the Joint Alberta-Canada Oil Sands Monitoring initiative, we aimed to assess cumulative effects of anthropogenic activities and exposure to natural bitumen geology on benthic macroinvertebrate assemblages in the lower Athabasca River. We examined associations among macroinvertebrates and environmental correlates, such as nutrients, ions, metals, polycyclic aromatic compounds, and total suspended solids. The study design included sites within and outside the mineable bitumen deposits, within and outside of the active mining and extraction area, and above and below municipal sewage effluents. We predicted observing a negative association between ecological condition of the river and exposure to natural bitumen and oil sands activity. However, contaminant concentrations in water and sediment were far below known toxicity thresholds, and benthic invertebrate assemblages in sites exposed to oil sands mining activities appeared more affected by nutrient enrichment from the MSE than contaminants from mining or natural bitumen. Although sites within the area of intense oil sands activity showed signs of mild environmental stress, assemblage pattern was more strongly associated with MSE nutrient enrichment than to diffuse contamination from either natural bitumen or oil sands mining. Enrichment likely increases food resources available to consumers, thereby potentially masking toxic responses of consumers to contaminants. Current regulations prohibit the direct release of oil sands contaminants to waterways, with diffuse atmospheric deposition of aerial emissions and fugitive dust the main contaminant pathways to freshwaters. As the storage capacity of tailings ponds is reached, this nutrient-contaminant pattern could change if the river receives the proposed direct release of oil sands process water. Focused investigation-of-cause studies are required to better assess the consequences of cumulative interactions and ecological effects of nutrients and contaminant exposure in this system.