The use of psychedelic substances is increasingly associated with nature-relatedness. We explore whether entheogenic uses of ayahuasca in settings co-produced between Indigenous and Western knowledges may also foster relationality and sustainability transformations across ontology, praxis, and epistemology. A survey with 74 English-speaking individuals who attended Amazonian healing ceremonies at the Takiwasi Center in Peru, along with 11 semi-structured interviews and a discussion circle revealed unexpected personal shifts towards relationality. Beyond the expected increase in nature-relatedness, participants also reported boundary dissolution and changes in their perceptions of self, leading them to experience nature and non-human beings as having spiritual or human-like agency. The blurring of perceived boundaries between themselves and nature also challenged the materialist ontologies in which they had been educated and socialized. In terms of both epistemologies and praxis, co-produced ayahuasca ceremonies enhanced relational thinking and embodiment of relationality. Inner-outer transformations ensued from the post-ceremonial integration of the ‘plant’s teachings’ into participants’ daily lives. We discuss our findings’ contributions to the emerging field of inner transformations and the relational turn in sustainability. Potential sustainability benefits of scaling plant-based ceremonies need to be measured against their impacts on the Amazon rainforest and its biocultures.