The rise in the global mean sea level (MSL) is a significant consequence of climate change, attributed to both natural and anthropogenic forces. This phenomenon directly affects the dynamic equilibrium of Earth’s oceanic and estuarine ecosystems, particularly impacting the Amazon estuary. In this study, a numerical model was employed to investigate the long-term impacts of MSL fluctuations on key hydrodynamic parameters crucial to regional environmental dynamics. Our investigation was based on scenarios derived from Representative Concentration Pathways (RCPs) and Coupled Model Intercomparison Project Phase 5 (CMIP5) projections, incorporating MSL variations ranging from 30 to 150 cm above the current mean level. Following careful calibration and validation procedures, which utilized observational and in situ data, notably from field expeditions conducted in 2019, our simulations unveiled significant impacts on certain hydrodynamic parameters. Specifically, we observed a pronounced increase in diurnal tidal amplitude (p < 0.05) within the upstream sections of the North and South channels. Additionally, discernible alterations in water renewal rates throughout the estuary were noted, persisting for approximately 2 days during the dry season (p < 0.05). These findings provide valuable insights into the vulnerability of key parameters to hydrologic instability within the Amazonian coastal region. In conclusion, this study represents a pivotal scientific endeavor aimed at enhancing the preservation of aquatic ecosystems and advancing the environmental knowledge of the Lower Amazon River, with the goal of proactively informing measures to safeguard the current and future sustainability of these vital ecosystems.