The Mississippi River represents a major commercial waterway, and periods of anomalously low river levels disrupt riverine transport. These low-flow events occur periodically, with a recent event in the fall of 2022 slowing barge traffic and generating sharp increases in riverine transportation costs. Here we combine instrumental river gage observations from the lower Mississippi River with output from the Community Earth System Model v2 Large Ensemble (LENS2) to evaluate historical trends and future projections of Mississippi River low streamflow extremes, place the 2022 low-flow event in a broader temporal context, and assess the hydroclimatic mechanisms that mediate the occurrence of low-flows. We show that the severity and duration of low-flow events gradually decreased between 1950 and 1980 coincident with the establishment of artificial reservoirs. In the context of the last ∼70 years, the 2022 low-flow event was less severe in terms of stage or discharge minima than other low-flow events of the mid- and late-20th century. Model simulations from the LENS2 dataset show that, under a moderate-high emissions scenario (SSP3-7.0), the severity and duration of low-flow events is projected to decrease through to the end of the 21st century. Finally, we use the large sample size afforded by the LENS2 dataset to show that low-flow events on the Mississippi River are associated with cold tropical Pacific forcing (i.e. La Niña conditions), providing support for the hypothesis that the El Niño-Southern Oscillation plays a critical role in mediating Mississippi River discharge extremes. We anticipate that our findings describing the trends in and hydroclimatic mechanisms of Mississippi River low-flow occurrence will aid water resource managers to reduce the negative impacts of low water levels on riverine transport.