Wheat is one of Ethiopia's foremost important cereal crops in terms of area coverage and volume produced. However, the production and productivity of wheat is constrained by various biotic and a biotic stresses, among which wheat yellow rust disease caused by Puccinia striiformis f.sp.tritici is the one. Field experiments were conducted to develop integrated wheat yellow rust management strategy based on optimal frequency of fungicide application and wheat varieties combination at hotspot environments of Meraro and Bekoji, Arsi zone, in 2017 main cropping season. Treatments included two different fungicides, Epoxiconazole + Thiophanate-methyl and Propiconazole applied in two frequencies; and four bread wheat cultivars (Kubsa, Danda'a, Lemu and Wane), known for their differential reaction to the disease. Unsprayed controls were also included for comparison purposes. The experiment was laid out in randomized complete block design in factorial arrangement with three replications. Terminal severity levels up to 13%, 37%, 53% and 90% at Bekoji, and 11.67%, 53.3%, 58.33%, 92% at Meraro were recorded on the unsprayed varieties of Wane, Lemu, Danda'a and Kubsa, respectively. Twice application frequency of Epoxiconazole + Thiophanate-methyl resulted in a significant (P<0.01) grain yield increment of up to 95.3%, 76.4%, and 1086.8% at Bekoji and 129.7%, 135.5%, 2883.2% at Meraro on unsprayed plots of Lemu, Danda'a, and Kubsa, respectively. But yield increments as a result of fungicide applications were relatively lower (29.8% and 65.9% at Bekoji and Meraro, respectively) on the resistant variety Wane. Twice application of Epoxiconazole + Thiophanate-methyl at 15 days interval starting from the appearance of disease has proved the most effective in terms of reducing the level of stripe rust, and increasing grain and crop biomass yield. The current findings demonstrate the role fungicides and host resistance may play in effectively managing stripe rust of wheat. However, further research is needed to come up with other management options to sustainable and cost effective manage the disease under different agro-ecological settings.