Chemical variability in the Mississippi River during water years 1989 to 1998 was evaluated using stream discharge and water‐quality data in conjunction with the DAFLOW/BLTM hydraulic model. Model simulations were used to identify subbasin contributions of water and chemical constituents to the Mississippi River upstream from its confluence with the Ohio and the Mississippi River and at the Atchafalaya Diversion in Louisiana. Concentrations of dissolved solids, sodium, and sulfate at the Thebes site showed a general decreasing trend, and concentrations of silica and nitrate showed a general increasing trend as the percentage of discharge from the Mississippi River upstream from Grafton increased. Concentrations of most chemical constituents in the Mississippi River at the Atchafalaya Diversion exhibited a decreasing trend as the percentage of water from the Ohio River increased. Regression models were used to evaluate the importance of the source of water to the water chemistry in the Mississippi River at Thebes and the Atchafalaya Diversion. The addition of terms in regression equations to account for the percent of water from sub‐basins improved coefficients of determination for predicting chemical concentrations by as much as nine percent at the Thebes site and by as much as 48 percent at the Atchafalaya Diversion site. The addition of source‐water terms to regression equations increased the estimated annual loads of nitrate and silica delivered from the Mississippi River Basin to the Gulf of Mexico by as much as 14 and 13 percent, respectively.