Rhamnus prinoides (Gesho) is grown in the homesteads of farmers in western Amhara. The leaves, twigs, and stems of Gesho are indispensable ingredients in traditional beverages. Its production has recently suffered from cedar rust caused by the fungus Gymnosporangium. To manage this disease, different fungicides have been recommended. Therefore, this research was designed to determine the rate and frequency of the use of the Natura 250 EW system for managing this disease in Gesho during 2020. Five application rates of Natura 250 EW and three spray frequencies were used as treatments to manage the disease in infected Gesho plants via the Randomized Complete Block Design (RCBD). Statistically significant differences (P ≤ 0.05) were found between treatments for most parameters. Among these 0.75 litter ha-1 treatments, two spray applications resulted in the lowest severity and greatest relative efficacy, followed by three spray applications of 0.50 litter ha−1 at Bahir Dar Zuria district. However, at Yilmana Densa district, the lowest severity and greatest relative efficacy were found for the 0.75 litter ha−1 spray, followed by the 0.50 litter ha−1 spray, compared with the other treatments. Even though 0.75 litter ha−1 had greater relative efficacy and lower disease severity than the other treatments, there was no statistically significant difference between the three sprays of 0.50 litter ha−1 at both locations. Therefore, three sprays of Natura 250 EW at 0.50 litter ha−1 in 15-day intervals should be recommended and demonstrated for the management of cedar rust disease on Gesho.