Fusarium head blight (FHB) is one of the destructive diseases in wheat-producing areas of the world. Field experiments were conducted during the 2019 main cropping season to determine an economically feasible time of application that consisted of fungicides and spray regimes to reduce FHB pressure and grain yield loss under field conditions at five locations in southern Ethiopia. The study was comprised of two fungicides and spray regimes. Totally seven treatment combinations were designed, including the unsprayed control plots. The field was designed by a randomized complete block design with four replications. Analysis of variance revealed interaction of fungicides and spray regimes significantly (P < 0.001) affected rates of disease progress, disease severity (DS), area under disease progress curve (AUDPC), and yield-related parameters. Lowest (0.0159 units day−1) and highest (0.0694 units day−1) disease progression rates were estimated from the application of Tebuconazole before disease onset and unsprayed control plots, respectively. Application of Tebuconazole before disease onset significantly reduced DS (67.68%), followed by application of Propiconazole + Tebuconazole before disease onset (67.16%) and Tebuconazole after disease onset (65.77%). Moreover, Propiconazole + Tebuconazole and Tebuconazole applications before disease onset considerably reduced AUDPC by 61.38%-days and 58.60%-days, respectively. The highest grain yield (5.02 t ha−1) was recorded from the application of Tebuconazole before disease onset. The grain yield loss of 44.22% was computed on an unsprayed plot compared to the plot protected with the application of Tebuconazole before disease onset. Overall, the application of fungicides' appropriate spray regimes reduces FHB pressure, and consequently, increases grain yields. However, the application of Tebuconazole before disease gave a better monitory advantage over the others. This could be suggested for the producers to manage FHB and enhance wheat production.