Background: Weaning is the process of liberating the patient from mechanical ventilation. It has been shown that no single weaning index can accurately predict a successful weaning process. Weaning by intensive care physicians’ bedside clinical discretion alone can sometimes lead to extubation failure. Yang–Tobin index, also known as the rapid shallow breathing index (RSBI) and integrative weaning index (IWI), are two of the most commonly used weaning indices in intensive care units (ICUs). We did a comparative study between the two indices for the prediction of successful weaning in mechanically ventilated patients. Materials and methods: We studied 115 patients who were mechanically ventilated for >48 hours and were ready for extubation. We recorded RSBI and IWI at 60 and 120 minutes for all patients, along with other physiological parameters like sequential organ failure assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, age, and mechanical ventilator parameters. The receiver operating characteristic (ROC) curves were calculated to evaluate the predictive performance of both the indexes. Results: We used two different indices (RSBI vs IWI) to predict successful extubation. An RSBI score of 25 was successfully extubated. Of 10 patients who experienced weaning failure and required reintubation within 48 hours, all patients had an IWI of <24. IWI was useful in detecting those patients who passed the spontaneous breathing trial (SBT) but needed reintubation afterward. Conclusion: Results showed both the Yang–Tobin index and IWI can successfully predict the weaning outcomes from the mechanically ventilated patient. The area under the curve (AUC) for the ROC curve for both indices was almost similar, suggesting both are comparable. IWI was useful in detecting those patients who passed the SBT but needed reintubation afterward.