Following the first COVID-19 case in Chiapas, Mexico in March 2020, the non-governmental organisation Compañeros En Salud (CES) and the state’s Ministry of Health (MOH) decided to join forces to respond to the global pandemic. The collaboration was built over 8 years of partnership to bring healthcare to underserved populations in the Sierra Madre region. The response consisted of a comprehensive SARS-CoV-2 infection prevention and control programme, which included prevention through communication campaigns to combat misinformation and stigma related to COVID-19, contact tracing of suspected and confirmed COVID-19 cases and their contacts, outpatient and inpatient care for patients with respiratory symptoms, and CES–MOH collaboration on anti-COVID-19 immunisation campaigns. In this article, we describe these interventions and their principal outcomes, as well as reflect on notable pitfalls identified during the collaboration, and we suggest a series of recommendations to prevent and mitigate their occurrence. As with many cities and towns across the globe, the poor preparedness of the local health system for a pandemic and pandemic response led to the collapse of the medical supply chain, the saturation of public medical facilities and the exhaustion of healthcare personnel, which had to be overcome through adaptation, collaboration and innovation. For our programme in particular, the lack of a formal definition of roles and clear lines of communication between CES and the MOH; thoughtful planning, monitoring and evaluation and active engagement of the communities served in the design and implementation of health interventions affected the outcomes of our efforts.