Background: Acute respiratory failure (ARF) is commonly managed with invasive mechanical ventilation (IMV). The majority of the time that a patient spends on IMV is in the process of weaning. Prediction of the weaning outcome is of paramount importance, as untimely/delayed extubation is associated with a high risk of mortality. Diaphragmatic ultrasonography is a promising tool in the intensive care unit, and its utility in predicting the success of weaning remains understudied. Methods: In this prospective-observational study, we recruited 54 ARF patients on IMV, along with 50 healthy controls. During a spontaneous breathing trial, all subjects underwent diaphragmatic ultrasonography along with a rapid shallow breathing index (RSBI) assessment. Results: The mean age was 41.8±17.0 and 37.6±10.5 years among the cases and control group, respectively. Demographic variables were broadly similar in the two groups. The most common cause of ARF was obstructive airway disease. The average duration of IMV was 5.41±2.81 days. Out of 54 subjects, 45 were successfully weaned, while nine patients failed weaning. Age, body mass index, and severity of disease were similar in the successful and failed weaning patients. The sensitivity in predicting successful weaning of percent change in diaphragmatic thickness (Δtdi%) >29.71% was high (93.33%), while specificity was 66.67%. The sensitivity and specificity of mean diaphragmatic thickness (tdi) end-expiratory >0.178 cm was 60.00% and 77.78%, respectively. RSBI at 1 minute of <93.75 had an equally high sensitivity (93.33%) but a lower specificity (22.22%). Similar results were also found for RSBI measured at 5 minutes. Conclusions: During the weaning assessment, the purpose is to minimize both premature as well as delayed extubation. We found that diaphragmatic ultrasonography, in particular Δtdi%, is better than RSBI in predicting weaning outcomes.