Background: Emerging zoonotic diseases represent a growing global threat, particularly for countries with constrained infrastructure and resources. There is a lack of qualitative research to understand community awareness, priorities, perceptions and practices around zoonotic risk, and how these are shaped by socio-cultural contexts, in Nepal. This study aimed to address these knowledge gaps by examining the implications for community engagement and co-production of community-level mitigatory strategies through a One Health approach in Nepal. Methods: This qualitative multimethod study used critical realist methodology, incorporating semi-structured individual and group interviews, photovoice, and unstructured observations with community members, and semi-structured interviews with policymakers and human and animal health-workers. I used thematic analysis informed by critical realism to analyse the data. Examination of issues surrounding zoonotic disease, awareness, and behaviours with communities, health experts, and policymakers, enabled a critical analysis of what people described and how this related to behaviours. Findings: Major themes on potential drivers of zoonotic disease and community knowledge of risk factors and prevention were: (i) disease awareness; and (ii) beliefs and behaviours. Participants were aware of diseases that might affect them, their family, or livelihood. Disease information usually spread informally between friend and family networks rather than through official channels. Use of traditional medicine was widespread, with discussion around whether this was an out-dated practice, and some describing this as pragmatic, since traditional healers are often more accessible and affordable than health facilities. Bushmeat consumption was something ‘others’ do, although some noted bushmeat could be medicinal and others discussed ‘clean’ and ‘dirty’ rodents. Hygiene practices were described as necessary to remove dirt but seldom linked explicitly to illness prevention. Major themes on community engagement and co-production of mitigatory activities were: (i) existing mitigatory practices; (ii) cultural factors; (iii) experience of community programmes; and (iv) community priorities and co-production. Community participants, despite strong opinions and desire to participate in disease control interventions, reported minimal or no attempts by intervention providers to engage them in design, implementation, evaluation, or accountability. Most had no experience of awareness programmes. Participants highlighted the importance of working in ‘local’ languages, respecting religious and cultural realities, relating initiatives to lived experience, and including community leadership. Through discussions with policymakers and healthcare practitioners, I aimed to identify how an effective One Health approach could realistically be operationalised in Nepal. Participants discussed themes such as One Health as a concept and opportunity; policy and politics; financing; and catalysts to raising awareness; power relations and multi-sectoral collaboration; community engagement; and collaboration with international partners; and lack of data and research on zoonotic disease that could inform a One Health control programme in Nepal. The government was perceived as generally supportive, endorsing a One Health plan with the incorporation of technical working groups involving relevant sectors. Participants recognised that healthcare in general is underfunded, with little data on zoonotic disease, resulting in a lack of awareness at governmental levels of the importance of the issues. Many participants were positive about the potential for the One Health strategy in Nepal. Similar barriers and enablers to progress were discussed by representatives of both human and animal health sectors, which suggests that there is a space for mutual understanding that could feed into a workable and effective method of implementing a One Health approach in Nepal. Conclusion: This PhD contributes to a small body of literature on community priorities, zoonotic disease threats, and One Health perspectives on working most effectively with(in) communities to address these threats. The findings illustrate the significance of acknowledging the multi-dimensional religious, cultural, educational, financial and social contexts in which people live, and how these influence their beliefs, needs and priorities. Implications from this PhD include the importance of promoting trust in communities through inclusion of prominent community members (community health volunteers, traditional medicine practitioners, women’s group leaders); the use of local languages; the acceptability of different media for interventions (theatre, drama); and the need to be realistic and pragmatic about available resources, to manage the expectations of community members. I have demonstrated the utility of both critical realism and participatory approaches (photovoice) in this type of research. Taken together, this PhD provides and develops insights to inform the design and implementation of research and interventions addressing drivers of zoonotic disease risk in conjunction with, and tailored to, communities in Nepal.