The coincidence of rising ozone concentrations ([O3]), increasing global temperatures, and drought episodes is expected to become more intense and frequent in the future. A better understanding of the responses of crop yield to elevated [O3] under different levels of drought and high temperature stress is, therefore, critical for projecting future food production potential. Using a 15-year open-air field experiment in central Illinois, we assessed the impacts of elevated [O3] coupled with variation in growing season temperature and water availability on soybean seed yield. Thirteen soybean cultivars were exposed to a wide range of season-long elevated [O3] in the field using free-air O3 concentration enrichment. Elevated [O3] treatments reduced soybean seed yield from as little as 5.3% in 2005 to 35.2% in 2010. Although cultivars differed in yield response to elevated [O3] (R), ranging from 17.5% to -76.4%, there was a significant negative correlation between R and O3 dosage. Soybean cultivars showed greater seed yield losses to elevated [O3] when grown at drier or hotter conditions compared to wetter or cooler years, because the hotter and drier conditions were associated with greater O3 treatment. However, year-to-year variation in weather conditions did not influence the sensitivity of soybean seed yield to a given increase in [O3]. Collectively, this study quantitatively demonstrates that, although drought conditions or warmer temperatures led to greater O3 treatment concentrations and O3-induced seed yield reduction, drought and temperature stress did not alter soybean's sensitivity to O3. Our results have important implications for modeling the effects of rising O3 pollution on crops and suggest that altering irrigation practices to mitigate O3 stress may not be effective in reducing crop sensitivity to O3.