(1) Background: COVID-19 disruptions offer researchers insight into how pandemics are at once biological and social threats, as communities struggle to construct meaning from novel challenges to their ontological status quo. Multiple epistemes, in which public health imperatives confront and negotiate locally derived knowledge and traditions, vie for legitimacy and agency, resulting in new cultural forms. (2) Methods: To investigate the context and construction of community responses, a systematic review of qualitative literature was conducted with the aim of evaluating those insights provided by empirical, social field research in low- and middle-income countries since the onset of COVID-19. Six scholarly databases were searched for empirical, qualitative, field-based, or participatory research that was published in peer-reviewed journals between December 2019 and August 2021. (3) Results: Twenty-five studies were selected for data extraction, following critical appraisal for methodological rigor by two independent reviewers, and were then analyzed thematically. Faced with unprecedented social ruptures, restrictions in social and physical mobility, and ever-looming uncertainties of infection, financial insecurity, stigma, and loss, communities worldwide reacted in multiple and complex ways. Pervasive misinformation and fear of social rejection resulted in noncompliance with pandemic sanctions, resistance, and increased isolation, allowing the spread of the disease. The meaning of, and understandings about, COVID-19 were constructed using traditional, religious, and biomedical epistemologies, which were occasionally in conflict with each other. Innovations and adaptations, through syntheses of traditional and biomedical discourses and practice, illustrated community resilience and provided models for successful engagement to improve public health outcomes. (4) Conclusion: Local context and community engagement were indispensable considerations when enacting effective public health interventions to meet the challenges of the pandemic.