Over 70% of Uganda is infested by the tsetse fly, which has negative effects on human and livestock health. From colonial to post-independent Uganda, the Government of Uganda has worked to eradicate the tsetse menace. Despite these efforts, recent veterinary reports from the Karamoja sub-region have indicated widespread tsetse invasion. This study investigated the potential impact of tsetse invasion on the socioecological resilience of pastoral communities in the Karamoja sub-region. Results indicated that tsetse invasion is spreading from north to south of Karamoja. The tsetse transmission route emerging from southern Karamoja is perceived to be a continuation of the tsetse belt from West Pokot, Kenya. Cases of livestock deaths, livestock abortions, decreased milk yields, restricted access to prime grazing lands, heightened human-wildlife conflicts and disruption on crop cultivation have been reported. A computed socioecological resilience index in the study area was positive but low. Owing to the transboundary characteristics of tsetse invasions and sources and the associated documented effects, an urgent, strategic and system-wide intervention should be undertaken to control the tsetse invasion in this sub-region. software, J.O. and J.P.M.; validation, A.E., J.O., J.P.M. and B.B.; formal analysis, A.E., J.O. and J.P.M.; investigation, A.E. and J.O.; resources, A.E.; data curation, J.O., J.P.M. and A.S.; writing-original draft preparation, A.E.; writing-review and editing, A.E., J.O., B.B., and A.S.; visualization, A.E., J.O., B.B. and A.S.; supervision, J.J.N.; project administration, A.E.; funding acquisition, A.E. and J.J.N. All authors have read and agreed to the published version of the manuscript.