The study was carried out to assess the economic burden of trypanosomosis in three villages of the Metekel zone in 2009. The disease was found to cause substantial economic losses through cattle mortality, drug purchase, and draft power loss of infected oxen. The farmers in the area were spending a significantly (p < 0.05) higher amount of money for the treatment of trypanosomosis than all other diseases combined. The overall mortality rate of cattle due to trypanosomosis was 4.4%. The mortality was significantly higher (p < 0.05) in an area where trypanosomosis prevalence was also higher. Many of the farmers prioritized losses of draft power as the most important impact of the disease. The overall prevalence of the disease was 12.1%. The disease burden was significantly (p < 0.05) higher in the rainy season than at other times of the year. In general, farmers had good knowledge on the signs and seasonality of trypanosomosis. Thus, tsetse suppression activities that involve the local community can be an important tool towards minimizing the economic burden of the disease in the area.