Global challenges, such as climate change, persistent poverty, and food insecurity are complex problems. These societal, environmental, and economic challenges cross scientific disciplines, communities, and geographies, requiring interdisciplinary, North–South solutions. Nevertheless, prevailing sustainability science responses are Western-centric. Some seminal studies have attempted to understand and engage with diverse knowledge systems. These include decolonial and Indigenous methodologies, such as “Two-Eyed Seeing”, which emphasizes the importance of using both Western and Indigenous knowledge to gain a more comprehensive understanding of the world, and participatory action research, which highlights the importance of involving participants in the research process and promoting social change through collaborative effort. However, apart from in-country research collaborations with traditional Indigenous knowledge, most North–South studies overlook the role or influence of Western-centric views and therefore fail to recognize and incorporate diverse worldviews and knowledge systems. This may, in part, reflect the tendency to categorize research into disciplinary silos, but more likely is the unintentional, yet prevalent, view that Western science is “objective and neutral.” As more scholars from multiple disciplines and geographies focus on interdisciplinary North–South research, it is critical that researchers reflect on dominant research approaches and knowledge production. Studies can co-construct, reproduce, or control the forms of knowledge generated—whether intentional or unintentional. This paper presents an organizing framework to help researchers navigate, understand, and engage with diverse forms of knowledge in undertaking North–South research. The framework draws on empirical observations from the authors’ interdisciplinary research and from empirical cross-cultural literature. It comprises three contextual levels of influence, featuring guiding principles and subsequent practical actions researchers can use to navigate the complexities of knowledge co-construction in North–South research.