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Background: This study analyzed weaning characteristics and assessed the association of clinical and ultrasonographic indices—maximum inspiratory pressure (MIP), rapid shallow breathing index (RSBI), peak flow expiratory (PFE), diaphragm-thickening fraction (DTF), diaphragm thickness (DT), diaphragm excursion (DE), diaphragm-RSBI (D-RSBI), and lung ultrasound (LUS) patterns—with weaning failure. Methods: This retrospective cohort study included critically ill COVID-19 patients aged 18 and older who had been on invasive mechanical ventilation for at least 48 h and undergoing weaning. Exclusion criteria included absence of ultrasound assessments, neuromuscular diseases, and chronic cardio-respiratory dysfunction. Results: Among 61 patients, 44.3% experienced weaning failure, 27.9% failed the spontaneous breathing trial (SBT), 16.4% were re-intubated within 48 h, and 28% required tracheostomy. Weaning failure was associated with prolonged ventilation (29 vs. 7 days, p < 0.001), extended oxygen therapy, longer ICU stays, and higher ICU mortality. These patients had higher pressure support, lower oxygenation levels, a higher RSBI, and a lower MIP. While PEF, DTF, DE, and D-RSBI showed no significant differences, both right and left diaphragm thicknesses and the inspiratory thickness of the left diaphragm were reduced in failure cases. LUS scores were significantly higher before and after SBT in the failure group. Bivariate analysis identified RSBI [OR = 1.04 (95% CI = 1.01–1.07), p = 0.010], MIP [OR = 0.92 (95% CI = 0.86–0.99), p = 0.018], and LUS [OR = 1.15 (95% CI = 0.98–1.35), p = 0.025] as predictors of weaning failure; however, these associations were not confirmed in multivariate analysis. Conclusions: Ultrasound provides supplementary information during weaning, but no definitive association between ultrasound indices and weaning failure was confirmed in this study. [ABSTRACT FROM AUTHOR]