Ratios of nitrogen (N), phosphorus (P), and dissolved silica (DSi) influence how algal communities respond to nutrient loading, and DSi limitation can facilitate cyanobacterial dominance. The indicator of coastal eutrophication potential (ICEP), described previously by other researchers, predicts production by diatoms vs. nonsiliceous taxa based on deviation of nutrient loads from the Redfield ratio of 106C:16 N:20Si (N‐ICEP) or 106C:1P:20Si (P‐ICEP). The ICEP was calculated for the Mississippi‐Atchafalaya River basin, and four subbasins: the Ohio‐Tennessee, Missouri, Upper Mississippi, and Arkansas‐Red basins from 1979 to 2015. The P‐ICEP indicated a stoichiometric imbalance that favored cyanobacteria for all but the Arkansas‐Red subbasin. The N‐ICEP indicated conditions favorable for cyanobacteria in the Upper Mississippi, Ohio‐Tennessee, and the northern Gulf of Mexico. Agriculture is the predominant land use in the Upper Mississippi and Ohio‐Tennessee subbasins and these subbasins controlled the stoichiometry of the nutrients delivered to the northern Gulf of Mexico. The imbalance in N, P, and DSi inputs to the Gulf was greatest during spring and early summer, and in most years transitioned to favoring diatoms by August or September. Comparing the 1980–1994 and 2001–2015 periods, there was a significant increase in the P‐ICEP for the Upper Mississippi, Ohio‐Tennessee, and Missouri subbasins that appeared to arise mainly from increased P loading to surface waters in the those basins. The ICEP revealed patterns in stoichiometry of N, P, and DSi loads among the major tributaries to the Mississippi River, and an increasing risk of cyanobacterial blooms for inland waters in much of the Mississippi‐Atchafalaya River basin.