Public health measures aimed at reducing the spread of COVID-19 can have significant, unintended impacts on livelihoods. In this paper, we assess the impacts of responses to the COVID-19 pandemic on aquaculture farmers in five countries in the Mekong Region. A total of 1,019 farmers were surveyed (June–August 2020). The COVID-19 pandemic reduced farmer mobility, disrupted input and produce logistics, and reduced consumer demand, which in turn, reduced net income relative to expectations and increased the likelihood of making a net loss in the first half of 2020. Large aquaculture farms were more likely to experience adverse impacts from higher input prices and lower fish market prices than small farms. Intensive and commercial farms were more likely to be affected by supplier and buyer logistic disruptions. Coping responses included adjustments to stocking practices, reducing labor inputs, finding new markets, drawing on savings, and borrowing money. Large farms were more likely to seek new markets and borrow money. Easier loan conditions and direct cash handouts by governments helped in some locations and were desired in others. Significant differences among countries in impacts and responses reflect market and trade dependencies, as well as government capacity and willingness to support the aquaculture industry.