Cross-sectional serological study and questionnaire survey were conducted in Borana pastoral and agro-pastoral area to determine seroprevalence and risk factors associated with foot-and-mouth disease (FMD) infection and to assess community perceptions as to importance of the disease. A multistage random sampling was carried out to select cattle for seroprevalence and households for interviews. Totally, 768 sera were collected from 111 herds. The overall individual level seroprevalence of 23.0% (n = 177) and herd level seroprevalence of 58.6% (n = 65) were recorded using 3ABC ELISA test. The variation of individual level seroprevalence in districts were statistically significant (P < 0.05) which was 29.9% in Arero, 24.0% in Yabello, and 15.7% in Teltele. From multivariate logistic regression analysis, herd size and age were seen to be significantly (P < 0.05) associated with FMD seroprevalence. The result of the questionnaire survey based on 120 respondents indicated that, the daily milk yield of cows infected with FMD during outbreaks is reduced to an average of 0.5 L for 25.5 days while cows developing heat-intolerance syndrome after acute infection gave an average 0.67 L for 3.8 months and their calving interval prolonged about 12 months. The questionnaire survey in agro-pastoral area of Borena also indicated that FMD-infected oxen remained off-plough for one season when outbreaks occur in cropping time, whereas heat-intolerant oxen were no longer used for traction. These findings of the present study indicated that FMD is a highly prevalent and economically important disease in the Borana pastoral and agro-pastoral production systems which need effective control strategy for the disease.