Diagnosing mesothelioma is difficult because the symptoms are similar to those of many other conditions. Diagnosis begins with a review of the patient's medical history because a history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical exam is also performed, followed by chest X-ray and lung function tests. The X-ray may reveal pleural thickening which is commonly seen after asbestos exposure. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytology, if this fluid is aspirated with a syringe. For pleural fluid, this is done by a pleural tap or chest drain. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made.

If cytology is positive or a plaque is suspicious, a biopsy is needed to confirm a diagnosis of mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples.

If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small opening in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.