Mesotheliomas are relatively rare and affect many animal species but have not been reported in donkeys (Equus asinus). Here we report a case of bicavitary epithelioid mesothelioma in a 33-year-old female donkey presented with weight loss, lethargy and anorexia. Physical examination revealed tachycardia, ileus and delayed capillary refill time. The animal was humanely euthanized and submitted for necropsy. Macroscopic examination revealed cachexia, 24.5 L of serosanguineous peritoneal effusion, 500 ml of serosanguineous pleural effusion and multifocal to coalescing exophytic, white, occasionally haemorrhagic, pinpoint to 5 × 5 × 2 cm nodules on the pleural and peritoneal surfaces and occasionally infiltrating into viscera. Histopathology of the omentum revealed an infiltrative, unencapsulated, poorly demarcated and moderately cellular neoplasm composed of cuboidal to polygonal cells arranged in acini, tubules and nests and, rarely, micropapillary projections, on a moderate fibrovascular stroma. Neoplastic cells had variably distinct cell borders, abundant eosinophilic granular to indistinctly vacuolated cytoplasm, a pleomorphic, central nucleus with finely stippled to marginated chromatin and up to three occasionally very large and distinct magenta nucleoli. There was marked anisocytosis and anisokaryosis and frequent mitoses. Neoplastic cells had diffuse and strong cytoplasmic vimentin immunolabelling and most also had moderate cytoplasmic immunolabelling of cytokeratin. Macroscopic, histopathological and immunohistochemical examinations were consistent with a bicavitary epithelioid mesothelioma, a rare neoplasm in domestic animals that has not been reported in the donkey. Dual vimentin and cytokeratin immunopositivity has been reported in other neoplasms in domestic animals, including ovarian, pulmonary and hepatocellular carcinomas, but no evidence of a primary carcinoma or of any other primary neoplasm was identified in this animal.