Indicators of wildlife health are important elements of a comprehensive approach for assessing and monitoring trends of methyl mercury (MeHg) contamination in the environment. River otters (Lontra canadensis) have been used as a model species for toxicological studies on the effects of MeHg bioaccumulation due to their position as an apex predator in aquatic systems and sensitivity to environmental disturbance. Although laboratory studies suggest that sublethal MeHg exposure may have detrimental effects on wildlife they are limited in their ability to reflect real world exposure and forecast population level effects. Few studies have identified the threshold at which MeHg exposure results in a population-level effect for wild populations of river otters in marine or fresh-water systems. We used a series of data sets collected over a 7-year period for river otter populations in central British Columbia, Canada, to assess mercury concentrations (river otter fur) and measurements of population status and health relative to a lake with an inactive and reclamated mercury mine along its shoreline (Pinchi Lake). We used a combination of remote cameras, marked individuals, hair snares, and scat counts/inventories to collect measurements of population status and health including: activity levels, population estimates, sex ratios, group sizes, litter sizes, behaviour, stress hormones, diet, and habitat quality. We found that mercury concentrations in river otter inhabiting Pinchi Lake were significantly higher than all other lakes in the study, and were also high relative to other areas in Canada and the United States. We did not, however, detect significant differences between the two lakes in many of the population parameters measured. We discuss the knowledge gaps and challenges of identifying the effects of MeHg for wild populations of mammals, determining sensitive and appropriate methods for measuring these effects, and the implications of our results for monitoring the impacts of natural resources activities. Detailed studies on population effects across a range of exposure and background conditions are required to address these data deficiencies. Typically, river otters are not included as monitoring species in environmental assessments even though their value as an indicator of anthropogenic contaminants has clearly been documented. We encourage inclusion of river otters in environmental assessments pre-, during -, and post-industrial activities as a measure of pollutant exposure and bioavailability as well as a critical first step in addressing knowledge gaps associated with contaminants and its effects on populations.