Introduction Pleural effusion is a challenging diagnosis at times, especially due to the overlap of symptoms in effusions of various etiologies. In this study, we aimed to identify if pleural fluid adenosine deaminase (ADA) or serum C-reactive protein (CRP) can be used as an additional novel biomarker for ADA in diagnosing tubercular, parapneumonic, and malignant pleural effusions. Materials and methods A prospective, observational, cross-sectional study was conducted on 79 patients diagnosed with tubercular, parapneumonic, or malignant pleural effusion from August 2022 to April 2024 at the Department of Respiratory Medicine at Dr.D. Y. Patil Medical College,Hospital&Research Centre, Pimpri, Pune. The pleural fluid ADA/serum CRP ratio was identified in each group, and analysis was done to compare the ratio in each group. The correlation with pleural fluid ADA was also identified. Results A total of 79 patients were enrolled in this study. Out of these patients, 53 (67.1%) were identified as having tubercular pleural effusion, 10 (12.7%) patients had parapneumonic effusion, and 16 (20.3%) had malignant pleural effusion. For malignant effusions, the area under the curve (AUC) using the receiver operating characteristic (ROC) for the ADA/CRP ratio was observed to be 0.862. Sensitivity was 87.50%and specificity was 82.54% at a cut-off value of ≤0.5. The positive predictive value was found to be 56%, and the negative predictive value was found to be 96.3%. For parapneumonic effusions, the AUC using the ROC for the ADA/CRP ratio was observed to be 0.880. Sensitivity was 100%and specificity was 69.57% at a cut-off value of ≤0.67. The positive predictive value was found to be 32.3%, and the negative predictive value was found to be 100%. For tubercular effusions, the AUC using the ROC for the ADA/CRP ratio was observed to be 0.955. Sensitivity was 92.45%and specificity was 88.46% at a cut-off value of >0.54. The positive predictive value was found to be 94.2%, and the negative predictive value was found to be 85.2%. The Pearson correlation coefficient (r) of 0.633 indicates a moderately strong positive linear relationship between ADA and ADA/CRP levels. Conclusion The pleural fluid ADA-to-serum CRP ratio can be used as a useful diagnostic tool for differentiating between tubercular, parapneumonic, and malignant pleural effusions. ADA/CRP ratio has added diagnostic value over ADA. In clinically puzzling scenarios, the ADA/CRP ratio can be a cost-effective tool before opting for a more expensive and invasive procedure, which is also often difficult to obtain in resource-limited healthcare settings. More research with a larger sample size is indicated to incorporate the ADA/CRP ratio as an added diagnostic tool along with ADA.