Background In December 2018, an outbreak of an unknown disease was reported to affect different animal species largely high number of small ruminant from Tumbio village in Korem town of southern Tigray. This study investigated the clinical characteristics, frequency (place, time, sex, age, physiological states), and primary causal agent(s) of outbreak. Results A total of 1966 cases occurred between 28 November and 21 December 2018, of which 1880 died, making a case fatality rate of 95.6%. The cases presented with inappetance (n = 953), thirsty (n = 833), pale mucous membrane (n = 676), bottle jaw (n = 424), swollen tail (n = 398), ascites (n = 309), suddenly died (n = 324), and diarrhea (n = 205). The responsible source of exposure was Minchae Bahri (pasture land). Excluding young suckling sheep which did not start grazing all groups of sheep were at risk. Even if, mixed parasitic infections were observed all samples processed parasitological were positive for immature liver flukes. Based on microbiologically finding Clostridium was isolated from 41(82%) samples. The necropsy and histopathology findings showed that liver is the most injured organ. The immediate interventions were not effective in controlling the outbreak. Conclusions Clinical presentation, immature liver flukes in all processed samples, high level of isolated Clostridium, necropsy and histopathology findings adducts among the cases support the causal role of acute fascioliasis complicated with Clostridium species. Community level awareness, integrated control measure and building diagnostic capacity of district level animal health experts and clinicians is needed.