To investigate the effects of respiratory mechanics-guided sedation strategy on diaphragm function in chronic obstructive pulmonary disease (COPD) patients treated with mechanical ventilation (MV). A prospective study was conducted. Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) received invasive MV who were admitted to the Affiliated Huxi Hospital of Jining Medical University from May 2020 to May 2021 were enrolled. The patients were divided into observational group and control group by random number table method. All patients were intubated for MV, and received bronchodilators, glucocorticoid, anti-infectives, expectorant, nutritional support, analgesia and sedation. The sedatives were dexmedetomidine combined with propofol, and the analgesics were sufentanil in both groups. Respiratory mechanics monitoring was performed every 6 hours in the observational group, and the depth of sedation was adjusted according to the parameters of respiratory mechanics: when airway resistance (Raw) > 20 cmH2O×L-1×s-1, deep sedation was given to maintain Richmond agitation-sedation scale (RASS) ≤ -3; when the Raw was 10-20 cmH2O×L-1×s-1, the initial depth of sedation maintained to reach the RASS score of -2-0; when Raw < 10 cmH2O×L-1×s-1, withdrawn the sedation, or given light sedation, and maintained the RASS score of -2-0. While the control group received light sedation. The patients' diaphragmatic excursions (DE) was measured by bedside ultrasound, tidal volume (VT) and respiratory rate (RR) were recorded, and the diaphragmatic rapid shallow breathing index (D-RSBI, D-RSBI = RR/DE) and diaphragmatic excursion efficiency (DEE, DEE = VT/DE) were calculated. The differences in DE, D-RSBI, and DEE before and 3 days and 5 days of treatment between the two groups were compared. The difference in the RASS score within 3 days of sedation between the two groups was compared. The differences in the duration of MV and 28-day mortality between the two groups were compared. A total of 96 patients were selected. Six patients were excluded due to delirium or the duration of MV shorter than 3 days. Finally, 90 patients were enrolled, with 46 in the observational group, and 44 in the control group. There were no statistically significant differences in DE, D-RSBI or DEE before treatment between the two groups. After treatment, D-RSBI in both groups was gradually decreased, and DEE was gradually increased with time. The D-RSBI at 3 days and 5 days of treatment in the observational group were significantly lower than those in the control group (times×min-1×mm-1: 1.73±0.48 vs. 1.96±0.35 at 3 days, 1.45±0.64 vs. 1.72±0.40 at 5 days, both P < 0.05), and DEE were significantly higher than those in the control group (mL/mm: 19.7±4.3 vs. 17.1±3.9 at 3 days, 25.8±5.6 vs. 22.9±5.4 at 5 days, both P < 0.05). There was no significant difference in DE at all time points between the two groups. The RASS scores within 2 hours of sedation in the observational group were significantly lower than those in the control group (1 day: -3.78±0.92 vs. -2.34±0.68, 2 days: -2.87±1.04 vs. -2.43±0.79, both P < 0.05), while no statistical difference at 3 days was found between the two groups. The duration of MV in the observational group was significantly shorter than that in the control group (days: 5.78±2.01 vs. 6.84±2.27, P < 0.05). One patient died in each of the control group and the observational group, and there was no significant difference in the 28-day mortality between the two groups (2.3% vs. 2.2%, P > 0.05). For AECOPD patients undergoing MV, respiratory mechanics-guided sedation strategy can reduce D-RSBI, increase DEE, shorten the duration of MV, and have a certain protective effect on the diaphragm.