Objective: To analyze the value of adenosine deaminase (ADA) level and monocyte ratio in pleural effusion to differentiate tuberculous pleurisy from malignant effusion and empyema. Methods: One hundred fifteen patients with pleural effusion admitted to our hospital from January 2019 to January 2020 were selected and divided into the tuberculous pleurisy group (n = 68), the malignant pleural effusion group (n = 25), and the empyema group (n = 22) by pathological examination. After admission, all patients underwent pleural puncture and drainage or catheterization. The first pleural effusion was collected and placed in the collection tube for ADA, CA125, nucleated cell count and single-factor analysis. The values of ADA, CA125, nucleated cell count and monocyte ratio in each group were compared. An ROC curve was used to analyze the value of ADA and CA125 in differentiating tuberculous pleurisy from malignant effusion and empyema. Results: The proportion of monocytes in pleural effusion of the tuberculous pleurisy group and the malignant pleural effusion group was significantly higher than that of the empyema group, and the number of nucleated cells was significantly lower than that of the empyema group; the proportion of monocytes in pleural effusion of the tuberculous pleurisy group was significantly higher than that of the malignant pleural effusion group, and the number of nucleated cells was significantly lower than that of the malignant pleural effusion group (P<0.05). The ADA of the tuberculous pleurisy group and the malignant pleural effusion group was significantly lower than that of the empyema group, and CA125 was significantly higher than that of the empyema group; ADA of the tuberculous pleurisy group was significantly higher than that of the malignant pleural effusion group, and CA125 was significantly lower than that of the malignant pleural effusion group; the difference was statistically significant (P<0.05). ROC curve analysis showed that the AUC of ADA in the diagnosis of tuberculous pleurisy was 0.785, the AUC of monocyte ratio in the diagnosis of tuberculous pleurisy was 0.685, the AUC of combined diagnosis of tuberculous pleurisy with ADA was 0.845, the AUC of ADA diagnosis of malignant effusion was 0.815, the AUC of monocyte ratio in the diagnosis of malignant effusion was 0.715, and the AUC of combined diagnosis of malignant effusion was 0.925. Conclusion: The level of ADA and the proportion of monocytes in pleural effusion can be used as important test indexes to distinguish tuberculous pleurisy from malignant effusion and empyema, and the combination of the two has the highest value and can be widely used in clinical practice.