BACKGROUND: Foot-and-mouth disease (FMD) is highly contagious and results in a high economic loss in the world. METHODS: A cross-sectional study was conducted from December 2021 to June 2022 in three selected districts to determine the sero-prevalence of FMD. A total of 384 cattle sera samples were collected and tested for antibodies against FMD virus using FMD NSP c-ELISA. RESULTS: The overall sero-prevalence of 25.3% was determined. Sero-prevalence of 31.0%, 32.37% and 4.5% was seen in the districts. Higher sero-prevalence was observed in Limmu Seka, and the disease was statistically significant in both Limmu Kosa and Limmu Seka districts (p <
0.05). Higher sero-prevalence was seen at Ambabesa Sadeka Peasant Association (42.86%). However, except Ambabesa Sadeka peasant association (PA), there was no statistically significant association (p >
0.05) of FMD occurrence among the nine PAs. Higher sero-prevalence was recorded in females (33.65%), old age (39.1%), poor body condition (43.0%) and herd size (43.1%). Therefore, sex, age, body condition of the animals and herd size showed significant association (p <
0.05) in the occurrence of FMD in the study areas. Purchased animals were highly infected (56.4%), and there was also a statistically significant association in the origin of the animals (p <
0.05). CONCLUSION: Overall, FMD is an economically important disease in the study areas. RECOMMENDATION: Further studies are warranted to characterize FMD virus serotypes in the areas and investigation in wildlife and small ruminants is needed to determine their roles in FMD virus maintenance and transmission.