ABSTRACT: Soybean (Glycine max L. Merrill) is an economically important commodity for United States agriculture. Nonetheless, the profitability of soybean production has been negatively impacted by soybean diseases. The economic impacts of 23 common soybean diseases were estimated in 28 soybean-producing states in the U.S., from 1996 to 2016 (the entire data set consisted of 13,524 data points). Estimated losses were investigated using a variety of statistical approaches. The main effects of state, year, pre- and post-discovery of soybean rust, region, and zones based on yield, harvest area, and production, were significant on "total economic loss" as a function of diseases. Across states and years, the soybean cyst nematode, charcoal rot, and seedling diseases were the most economically damaging diseases while soybean rust, bacterial blight, and southern blight were the least economically damaging. A significantly greater mean loss (51%) was observed in states/years after the discovery of soybean rust (2004 to 2016) compared to the pre-discovery (1996 to 2003). From 1996 to 2016, the total estimated economic loss due to soybean diseases in the U.S. was $95.48 billion, with $80.89 billion and $14.59 billion accounting for the northern and southern U.S. losses, respectively. Over the entire time period, the average annual economic loss due to soybean diseases in the U.S. reached nearly $4.55 billion, with approximately 85% of the losses occurring in the northern U.S. Low yield/harvest/production zones had significantly lower mean economic losses due to diseases in comparison to high yield/harvest/production zones. This observation was further bolstered by the observed positive linear correlation of mean soybean yield loss (in each state, due to all diseases considered in this study, across 21 years) with the mean state wide soybean production (MT), mean soybean yield (kg ha-1), and mean soybean harvest area (ha). Results of this investigation provide useful insights into how research, policy, and educational efforts should be prioritized in soybean disease management.