The Mekong basin’s fisheries are important sources of food, income, and livelihoods for millions of people in six countries. However, fish yields appear to have declined in recent years according to reports from local fishers throughout the basin. It is important to understand the factors driving the decline in fisheries so that they can be adequately managed. We analysed interview data from 1020 fishers in the Mekong Delta in Vietnam in 2014 to identify trends in catch rates and the possible factors driving the trends. Most of the fishers (68–90%) reported that their catch rates had declined over the previous five years, although some fishers stated that their fish catches had remained stable or even increased. They identified eleven factors that they believed contribute to declines in fish catches, among which the use of illegal gears and overfishing were considered most important, with other factors relatively unimportant. Separately, long-term datasets (1995–2016) showed a general decline in commercial fish catches, which was positively correlated with peak water levels (which indicate flood levels), and negatively correlated with the intensification of rice farming, especially where flooding has been prevented to allow a third annual rice crop. Some data suggests that fishing effort has declined significantly in recent years, so an apparent downward trend in catches is not likely to be a result of overfishing as believed by fishers, which suggests that fishers are not aware of or under-rate the significance of hydrological and land-use/landscape changes. Due to the exceptional importance of the Mekong fishery and the interactions with other more dominant sectors, improved data collection is required to quantify changes in fisheries that result from land use and hydrological changes, and to guide planning which would better resolve competing demands for water and land use.