Background. The COVID-19 pandemic and government-led interventions to tackle it have had life-changing effects on vulnerable populations, especially rural and urban slum dwellers in developing countries. This ethnographic study explored how the Ghanaian government’s management of COVID-19, socio-cultural factors, infrastructural challenges, and poverty influenced community perceptions, attitudes, and observance of COVID-19 prevention measures in Ghana. Methods. The study employed focused ethnography using in-depth interviews (IDIs), focus group discussions (FGDs), and nonparticipant observations to collect data from an urban slum and a rural community as well as from government officials, from October 2020 to January 2021. The data were triangulated and analyzed thematically with the support of qualitative software NVivo 12. All ethical procedures were followed. Results. The Ghanaian government’s strategy of communicating COVID-19-related information to the public, health-related factors such as health facilities failing to follow standard procedures in testing and tracing persons who came into contact with COVID-19-positive cases, poverty, and lack of social amenities contributed to the poor observance of COVID-19 preventive measures. In addition, the government’s relaxation of COVID-19 restrictions, community and family values, beliefs, and misconceptions contributed to the poor observance of COVID-19 preventive measures. Nevertheless, some aspects of the government’s intervention measures and support to communities with COVID-19 prevention items, support from nongovernmental organizations (NGOs), and high knowledge of COVID-19 and its devastating effects contributed to positive attitudes and observance of COVID-19 preventive measures. Conclusion. There is a need for the government to use the existing community structures to engage vulnerable communities so that their concerns are factored into interventions to ensure that appropriate interventions are designed to suit the context. Moreover, the government needs to invest in social amenities in deprived communities. Finally, the government has to be consistent with the information it shares with the public to enhance trust relations.