In the Tapajos River, Brazilian Amazon, fishing is an important activity, especially for low-income riverine populations. Unfortunately, the Tapajos River fish diversity and abundance are threatened by several anthropogenic drivers, including deforestation and overfishing. We modeled the lower Tapajos River's food web and simulated changes in biomass compartments as a response to increases in deforestation (loss of floodplain forest habitat) and on artisanal fishing pressure over 30 years. According to our simulations, the large-bodied species could be reduced drastically while small-bodied and fast-growing species could be favored by fishing effort increasing. The loss of floodplain forest is expected to cause a general decline (23%) of the total standing fish biomass. This reduction could reflect greater losses on species that are directly dependent on resources from the floodplain forests, such as fruits and seeds. These results indicated that the food web of the lower Tapajos River is structurally characterized by bottom-up control, through the use of basal resources, such as detritus (mostly from decomposing plants), fruits, seeds, terrestrial, and aquatic invertebrates. Furthermore, the simulations’ results highlight that the protection of the floodplain forest through the existing protected areas will be of essential importance in the future to maintain fish biomass, sustainable artisanal fishing, and improve the food security of Amazonian riverine inhabitants.