The Mississippi River is a vital economic corridor used for generating hydroelectric power, transporting agricultural products, and municipal and industrial water use. Communities, industries, and infrastructure along the Mississippi River face an uncertain future as it grows more susceptible to climate extremes. A key challenge is determining whether Mississippi river discharge will increase or decrease during the 21st century. Because the 20th century record is limited in time, paleoclimate data and model simulations provide enhanced understanding of the basin's hydroclimate response to external forcing. Here, we investigate how anthropogenic forcing in the 20th century shifts the statistics of river discharge compared to a Last Millennium (LM) baseline using simulations from the Community Earth System Model Last Millennium Ensemble. We present evidence that the 20th century exhibits wetter conditions (i.e., increased river discharge) over the basin compared to the pre-industrial, and that land use/land cover changes have a significant control on the hydroclimatic response. Conversely, while precipitation is projected to increase in the 21st century, the basin is generally drier (i.e., decreased river discharge) compared to the 20th century. Overall, we find that changes in greenhouse gases contribute to a lower risk of extreme discharge and flooding in the basin during the 20th century, while land use changes contribute to increased risk of flooding. The additional climate information afforded by the LM simulations offers an improved understanding of what drove extreme flooding events in the past, which can help inform the development of future regional flood mitigation strategies.