Fusarium head blight (FHB), a fungal disease of wheat caused by Fusarium graminearum, and its associated toxins, particularly deoxynivalenol (DON), are best managed by integrating multiple strategies. Experiments were established in 2011 and 2013 to evaluate the effects of integrating cultivar resistance, fungicide application, and grain harvesting strategy on FHB index (IND; field severity), DON, grain yield (YLD), and grain test weight (TW; weight per unit volume). Plots of two moderately resistant and two susceptible cultivars were either treated with 19% tebuconazole + 19% prothioconazole or left untreated, and then inoculated with F. graminearum. IND was rated as the mean percentage of diseased spikelets per spike. Separate subsets of the plots of each cultivar–treatment combination were harvested with one of two combine harvester configuration: C1 (the default, set at a fan speed of 1,375 rpm and a shutter opening of 70 mm) and C4 (modified, with the same fan speeds but a wider shutter opening of 90 mm). YLD and TW data were collected, and grain samples were rated for percent Fusarium-damaged kernels (FDK) and tested for DON. Results from linear mixed-model analyses showed that the cultivar–treatment interaction was significant for all FHB-related responses, with the magnitude of the difference in mean arcsine-square-root-transformed IND and FDK (arcIND and arcFDK) and log-transformed DON (logDON) between treated and untreated being higher for susceptible than moderately resistant cultivars. Plots harvested with the C4 combine configuration had significantly higher mean TW than those harvested with C1. Treated plots had significantly higher YLD and TW than untreated plots, regardless of cultivar and configuration. Relative to the reference management program (untreated, susceptible cultivar, harvested with C1), the greatest percent reduction in FDK and DON and increase in YLD was observed for programs that included moderate resistance and fungicide treatment. The greatest percent increase in TW relative to the reference was observed when C4 adjusted combine setting was integrated with resistance and fungicide. Overall, the most effective management programs all included fungicide treatment, two included moderate resistance, and two included C4 combine setting. Relative to the reference management program, these programs resulted in 30 to 51% reduction in total estimated price discount, $127 to 312 ha−1 increase in gross cash income, and economic benefit of $31 to 272 ha−1, depending on the level of FHB IND (5 to 15%), grain price ($118 to 276 metric ton−1), and fungicide application cost ($40 to 96 ha−1).