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In December 2018, an outbreak of an unknown disease was reported to affect sheep from Tumbio village in Korem town of southern Tigray. This study investigated the clinical characteristics, frequency, and primary causal agent(s) of the outbreak. Outbreak investigation was conducted using cross-sectional and longitudinal observation. Data on the animal infected, the exposure, predominant symptoms, risk group, and others were collected using structured questionnaire. Furthermore, from 50 randomly selective active cases sheep postmortem, parasitological, microbiological, and pathological examination were done. A total of 1966 cases occurred between November 28 and December 21, 2018, of which 1880 died, making a case fatality rate of 95.6%. The cases presented with inappetance, thirst, pale mucous membrane, bottle jaw, swollen tail, ascites, sudden death, and diarrhea. The responsible source of exposure was Menche Bahri (pasture land). Excluding young suckling sheep all sheep were at risk. Even if mixed parasitic infections were observed, all samples processed parasitologically were positive for immature liver flukes. Based on microbiological finding, Clostridium was isolated from 41 (82%) samples. Necropsy and histopathology findings showed that the liver is the most injured organ. The immediate interventions were not effective in controlling the outbreak. Clinical presentation, immature liver flukes in all processed samples, high level of isolated Clostridium, and necropsy and histopathology findings adducts among the cases support the causal role of acute fascioliasis complicated with Clostridium species. Community-level awareness, integrated control measures, and building diagnostic capacity of district level animal health experts and clinicians are needed. [ABSTRACT FROM AUTHOR]