This study aims to report a spontaneous and experimental intoxication in cattle by Melanthera latifolia (Asteraceae) for the first time, and to describe its epidemiological, clinical, and pathological findings. An outbreak of acute toxic hepatopathy in cattle occurred from December of 2021 to January of 2022 in a beef cattle farm from Rio Grande do Sul state, Southern Brazil, and resulted in 94 deaths from a herd of 430 animals. At necropsy, lesions consisted of enhanced lobular pattern of the liver, transmural gallbladder edema, and hemorrhages on the surface of multiple organs. The main microscopic lesion was marked hepatocellular necrosis in the centrilobular region associated with hemorrhage and infiltration of neutrophils. During the outbreak, multiple specimens of M. latifolia were noted in the paddocks where affected cattle were grazing and many showed signs of consumption. No other known acute hepatotoxic plants were found. Two 12-month-old steers were experimentally intoxicated with a single oral dose of the fresh plant (flowers, leaves, and less fibrous stalks). One bovine ingested a dose of 10 g/kg and was euthanized after 48 h, and the other ingested 15 g/kg and was euthanized 17 h later. Clinical signs, macroscopic, and microscopic lesions in both animals were similar to those observed in the spontaneous cases. Thus, this study demonstrates that M. latifolia was the cause of the outbreak of acute toxic hepatopathy with significant mortality in cattle. M. latifolia nor any plant of the genus Melantherahad ever been reported as toxic.