Ever closer to the brink of global environmental collapse, it is vital that we work collaboratively and collectively as global, national, and local communities to design multi‐scale change. Protecting future generations and reversing (or substantively slowing) the current trends requires rapid sustainable progress at the required scale. It is more urgent than ever we understand and more fully realise the power of transdisciplinary (Td) research to support sustainable practice. A defining factor of Td is the focus on collaboration and co‐design and the extent that participation and attention to local context is integral to the knowledge building. Specifically there is greater ability for community knowledge, values and aspirations to influence and shape research inquiries to effect meaningful change in real world decision‐making and outcomes. Business as usual (BAU) approaches that perpetuate unequal knowledge sharing and dismiss other forms of knowledge beyond traditional science no longer suffice. Transdisciplinary approaches seek to achieve and support sustainable change, but the extent of transformation required to meet ecological protection and regenerative sustainability needs very different operating models for knowing and doing science than the limited traditions of positivist science. However, these powerful defaults and operating paradigms are more deeply ingrained than we might realise, and hence challenges persist. This paper illustrates how Td science differs from typical research paradigms, particularly in terms of the underlying epistemology, the focus on knowledge/power, attention to boundaries and scope, and the degree to which local knowledge, context and community participation underpin the research process. Active conversations are required to better identify and overcome fundamental challenges for science and Td research approaches to support the necessary transformational change. Importantly, we suggest that Indigenous partnerships, knowledge and values are vital in achieving the potential of transdisciplinary research to provide transformational interventions to address complex social and environmental issues like pollution.