An increasing need for novel approaches to knowledge co-production that effectively and equitably address sustainability challenges has arisen in the twenty-first century. Calls for more representative and contextual co-production strategies have come from indigenous communities, scientific research forums, and global environmental governance networks. Despite calls to action, there are no systematic reviews that derive lessons from knowledge co-production scholarship to interpret their significance through the lens of a specific sociopolitical and cultural context. We conducted a systematic review of peer-reviewed and grey literature on knowledge co-production published from 2000 to 2020. Using a hybrid inductive and deductive thematic analysis, we identified two conceptual themes—guiding principles and approaches—to structure the synthesis and interpretation of 102 studies. We found that knowledge co-production studies often converged on four interrelated principles: recognition of contextual diversity bounding knowledge co-production, preemptive and intentional engagement with indigenous knowledge holders, formation of shared understanding of the purpose of knowledge co-production, and empowerment of knowledge holders throughout the co-production cycle. These principles manifested in multiple approaches for interpreting, bridging, applying, and distributing power amongst diverse knowledge systems rooted in different epistemologies. We filter these findings through the social–ecological context that frames an ongoing knowledge co-production project with Inuit communities in Nunatsiavut, Canada: the Sustainable Nunatsiavut Futures Project. Our review suggests that emerging forms of knowledge co-production principles and approaches yield immense potential in diverse contexts. Yet in many regions, including Nunatsiavut, principles alone may not be enough to account for systemic and contextualized issues (e.g., colonization and data sovereignty) that can present roadblocks to equitable sustainability science in the twenty-first century if left unaddressed.