Abstract The Mississippi River System (MRS) is one of the most important commercial routes in the world and its navigability is critical for anticipating potential disruptions in the global supply chain. Here we show that the navigability of the MRS has reduced since 1963, especially in the lower part of the basin. Based on analyses of daily stage time series and the associated conditions for navigation, we find that high rather than low water levels are the main culprits for the observed navigability issues. Moreover, not only have the navigable days decreased, but navigation without operational restrictions has also become more fragmented. Our findings provide basic information toward the development of strategies to mitigate potential negative effects in the U.S. navigation sector.