The exposure of freshwater-dependent coastal ecosystems to saltwater is a present-day impact of climate and land-use changes in many coastal regions, with the potential to harm freshwater and terrestrial biota, alter biogeochemical cycles and reduce agricultural yields. Land-use activities associated with artificial drainage infrastructure (canals, ditches, and drains) could exacerbate saltwater exposure. However, studies assessing the effects of artificial drainage on the vulnerability of coastal landscapes to saltwater exposure are lacking. We examined the extent to which artificial drainage infrastructure has altered the potential for saltwater intrusion in the coastal plain of eastern North Carolina. Regional spatial analyses demonstrate that artificial drainages not only lower the overall elevation in coastal landscapes, but they also alter the routing and concentration of hydrological flows.  Together, these factors have the potential to increase the total proportion of the landscape vulnerable to saltwater intrusion, not only in areas adjacent to drainage infrastructure but also in places where no artificial drainages exist due to large scale effects of flow rerouting. Among all land cover types in eastern North Carolina, wetlands are most vulnerable to saltwater exposure. Droughts and coastal storms associated with climate change potentially exacerbate vulnerability to saltwater facilitated by artificial drainage.