BACKGROUND: Vulnerable populations such as rural and urban-slum dwellers are more likely to suffer greatly from the deleterious effects of the novel Coronavirus disease 2019 (COVID-19). However, in Ghana, most COVID-19 mitigating packages are not focused on vulnerable populations. METHODS: Concurrent mixed methods design was used to examine the socio-economic and health effects of COVID-19 among rural and urban-slum dwellers in Ghana. Four hundred respondents were sampled for the quantitative arm of the study, while 46 In-depth Interviews (IDIs) were conducted with community members and government officials. Sixty-four community members participated in Focus Group Discussions (FGDs) and non-participant observation was carried out for three months. Quantitative data were analysed using frequencies, percentages, Pearson Chi2 and ordered logistic regression. Interviews were recorded using digital recorders and later transcribed. Transcribed data (IDIs, FGDs) and observation notes were uploaded onto a computer and transferred to qualitative software NVivo 12 to support thematic coding and analysis. RESULTS: Majority of the respondents confirmed the deleterious socio-economic and health effects of COVID-19 on jobs and prices of food. Other effects were fear of visiting a health facility even when unwell, depression and anxiety. Young people (18-32 years), males, urban-slum dwellers, married individuals, the employed and low-income earners (those who earn GHC10/$1.7 to GHC100/ $17), were more likely to suffer from the socio-economic and health effects of COVID-19. Urban-slum dwellers coped by relying on family and social networks for food and other basic necessities, while rural dwellers created locally appropriate washing aids to facilitate hand washing in the rural communities. CONCLUSION: COVID-19 and the government's mitigation measures had negative socio-economic and health effects on vulnerable communities. While vulnerable populations should be targeted for the government's COVID-19 mitigating packages, special attention should be given to young people (18-32 years), males, urban-slum dwellers, married individuals and low-income earners. Communities should be encouraged to maintain coping strategies adopted even after COVID-19.