Freshwater megafauna, such as sturgeons, giant catfishes, river dolphins, hippopotami, crocodylians, large turtles, and giant salamanders, have experienced severe population declines and range contractions worldwide. Although there is an increasing number of studies investigating the causes of megafauna losses in fresh waters, little attention has been paid to synthesising the impacts of megafauna on the abiotic environment and other organisms in freshwater ecosystems, and hence the consequences of losing these species. This limited understanding may impede the development of policies and actions for their conservation and restoration. In this review, we synthesise how megafauna shape ecological processes in freshwater ecosystems and discuss their potential for enhancing ecosystem restoration. Through activities such as movement, burrowing, and dam and nest building, megafauna have a profound influence on the extent of water bodies, flow dynamics, and the physical structure of shorelines and substrata, increasing habitat heterogeneity. They enhance nutrient cycling within fresh waters, and cross-ecosystem flows of material, through foraging and reproduction activities. Freshwater megafauna are highly connected to other freshwater organisms via direct consumption of species at different trophic levels, indirect trophic cascades, and through their influence on habitat structure. The literature documenting the ecological impacts of freshwater megafauna is not evenly distributed among species, regions, and types of ecological impacts, with a lack of quantitative evidence for large fish, crocodylians, and turtles in the Global South and their impacts on nutrient flows and food-web structure. In addition, population decline, range contraction, and the loss of large individuals have reduced the extent and magnitude of megafaunal impacts in freshwater ecosystems, rendering a posteriori evaluation more difficult. We propose that reinstating freshwater megafauna populations holds the potential for restoring key ecological processes such as disturbances, trophic cascades, and species dispersal, which will, in turn, promote overall biodiversity and enhance nature’s contributions to people. Challenges for restoration actions include the shifting baseline syndrome, potential human–megafauna competition for habitats and resources, damage to property, and risk to human life. The current lack of historical baselines for natural distributions and population sizes of freshwater megafauna, their life history, trophic interactions with other freshwater species, and interactions with humans necessitates further investigation. Addressing these knowledge gaps will improve our understanding of the ecological roles of freshwater megafauna and support their full potential for facilitating the development of effective conservation and restoration strategies to achieve the coexistence of humans and megafauna.