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Northern Sudan is an important corridor cluster between pools of foot-and-mouth disease virus (FMDV) in East and North Africa. It involves almost the whole border area with Egypt and represents a considerable part of a projected disease-free zone in Sudan. The study monitored FMD infection between 2016 and 2018 in Northern Sudan. Clinical and serological surveillance were carried out. Results largely confirmed previous reports that have described the relatively lower circulation of FMDV in the area than in other parts of the country. Clinical FMD was confirmed, once in the three years period, as serotype O of an unnamed lineage within the topotype East Africa 3 (EA3). Using serial testing (the ID ELISA and virus neutralization test), sero-prevalence estimates of serotype-specific antibodies in the two States of Northern Sudan ranged between 15.4% (serotype A) in the River Nile State to 3.4% (serotype SAT2) in the Northern State. Striking disparities between patterns of FMD in Northern Sudan and the rest of Sudan were observed. Unlike Western, Eastern, Central and Southern Sudan, no predominance of serotype O antibodies was detected in Northern Sudan. Concurrently, a serotype O isolate from Northern Sudan in 2016 was found to be of transboundary nature circulating in East and North Africa and in the Middle East (nt. id. > 99%); like serotype O that caused the last episode of disease in Northern Sudan in 2012. Molecular findings were compatible with the inferred low circulation of FMDV in Northern Sudan. Elsewhere in Sudan, endogenous serotype O viruses seemed to be circulating more unabated. It was concluded that low animal density and limited animal movement in Northern Sudan together with the high antibody levels against serotype O in immediately neighbouring States (Khartoum and Kassala) effectively decreased infiltration of endogenous O viruses.