The Covid-19 pandemic fundamentally disrupted lives worldwide, leaving significant social and economic consequences. This study examined the extent to which the pandemic affected rural households in the Vietnamese Mekong Delta in two dimensions, encompassing health and economic welfare; and the individual’s perception of the Covid-19 seriousness, as well as their coping strategies for this health disaster. Applying the ‘One Health’ approach, a single cross-sectional sample of 461 rural households was obtained, including information on household demography, productive resources, and Covid-19-related health issues in Tien Giang, Tra Vinh, and Can Tho. The findings are that (1) the Covid-19 pandemic significantly reduced household income while the Covid-19-related health issue was less severe; (2) the state financial support for rural households to mitigate the negative impacts of Covid-19 was marginal and unequal; and (3) the One Health approach attracts considerable attention from rural households. Accordingly, improving skills and knowledge is part of a long-term strategy to promote income extension in this region for economic recovery and preparation for future inevitable health shocks.