The health of fish is a primary indicator of ecosystem response in the Oil Sands Region of northeastern Alberta. However, industrial activity is accompanied by other stressors, such as the discharge of sewage, municipal activity, forest fires, and natural weathering and erosion of bitumen. To combat the spatial confounding influences, we examined white sucker (Catostomus commersonii) captured in the Athabasca River at sites over time (2011–2019) and included covariates to account for the possible sources of influence. The analyses suggest spatially heterogeneous influences of natural factors on fish, such as discharge and air temperature, but also the influence of sewage phosphorus and precipitation. Among the stressors examined here, precipitation may be the most complex and may include a mixture of sources including inputs from tributaries, urban activity, industrial development, and forest fires. Although suggestive, the attribution of variance and detection of changes are affected by sample sizes in some years; these analyses may have missed effects or misspecified important relationships, especially in males. Despite these limitations, the analyses suggest potential differences may be associated with precipitation and highlight the need to integrate robust information on known and suspected stressors in future monitoring of aquatic ecosystems in the oil sands region and beyond.