Objective: To investigate the predictive value of diaphragm thickening fraction (DTF) combined with cough peak expiratory flow (CPEF) on the success rate of weaning from mechanical ventilation. Methods: The clinical data of patients undergoing invasive mechanical ventilation via oral endotracheal intubation in the ICU of our hospital from January 2022 to December 2023 were studied. All patients underwent a 30-minute spontaneous breathing trial (SBT) using low-level pressure support ventilation (PSV) after meeting the clinical weaning screening criteria. Among them, 150 patients who met the clinical weaning criteria were weaned from the ventilator. They were divided into a successful weaning group (n=100) and a failed weaning group (n=50) based on the weaning outcome. Clinical data, including age, gender, APACHE II score, duration of mechanical ventilation, DTF, and CPEF, were collected from 150 patients. The differences in clinical data between the two groups were compared, and the correlation between DTF, CPEF, and the success rate of weaning was analyzed. Results: There were no significant differences between the two groups in gender ratio (χ2=0.884, P=0.347>0.05), age (t=0.350, P=0.727>0.05), and APACHE II score (t=1.295, P=0.197>0.05), but there was a significant difference in the duration of mechanical ventilation (t=3.766, P<0.001). The DTF and CPEF values in the successful weaning group were significantly higher than those in the failed weaning group (P<0.05). ROC curves were drawn to predict the weaning results using DTF, CPEF, and the combination of DTF and CPEF. The results showed that the specificity of the combination of DTF and CPEF was comparable to that of either metric alone, but the sensitivity and AUC were significantly higher than those of either metric alone. Conclusion: The combination of DTF and CPEF can be used as an effective indicator to evaluate the weaning efficacy of mechanically ventilated patients, which has important clinical significance for guiding clinical weaning treatment, improving the success rate of weaning, reducing the incidence of ventilator-associated pneumonia, and shortening the length of hospital stay.