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Cumulatively, the effects of resource extraction and climate change have the potential to cause an unprecedented change to the ecosystems and livelihoods of Indigenous communities in Canada’s northern regions. Maintaining environmental and community values in the presence of such change will require a comprehensive understanding of potential long-term risks and opportunities to prevent or mitigate risks at the regional level. However, assessing the cumulative impact and benefits of the multiple disturbances at the regional level is complex due to the interaction of numerous drivers, values, actors, assessment scales, planning, and decision-making processes. We develop an integrated risk and cumulative effects (CE) management methodology to inform regional assessment by combining conceptual modelling through bowtie analysis and quantitative scenario analysis using ALCES Online (AO) simulation. We applied the framework using a case example in the Ring of Fire region of northern Ontario, Canada, to assess the CE of climate change, land use change, and wildlife harvest on the moose (Alces alces)-wolf (Canis lupus)-caribou (Rangifer tarandus) prey-predator system. The bowtie risk analysis provided a mechanism to define the management problem by identifying threats that contribute to risk, associated consequences, and specific management strategies that could be pursued under legislative frameworks and changes to maintain the sustainable dynamics of the moose-wolf-caribou system (MWC). The AO simulation of different levels of development and moose harvest, as well a baseline scenario that excluded climate change and development, allowed for a comprehensive examination of the complex processes driving the social-ecological system. The scenario analysis suggests that moose harvest can promote balance in the MWC system but only if applied in a sophisticated manner that limits moose harvest in areas with high road density, increases moose harvest in more remote regions susceptible to moose population expansion with climate change, and prioritizes Indigenous moose harvest to ensure a sustainable supply of moose for subsistence harvest. The case example shows how conceptual and quantitative modelling can provide the strategic perspective required for regional assessment.