Abstract: Objective To analyze the clinical application of sedative drugs in Intensive Care Unit (ICU) patients with mechanical ventilation based on normal rest, to provide a referencefor its clinical care. Methods Sixty patients with ICU mechanical ventilation who were diagnosed and met in our hospital in January 2016 and January 2017 were divided into observation group (30 cases) and control group (30 cases) according to the random number table method. The patients in the control group were treated with routine intervention mode. The patients in the observation group adjusted the use of sedative drugs according to the normal rest. The sedative and analgesic depth of patients with mechanical ventilation was controlled by the Ricker Sedation-Agitation Scale (SAS) and the Critical-care Pain Observation Tool (CPOT). Comparison of the incidence of adverse events (ventilation time, ICU treatment time, systolic blood pressure, diastolic blood pressure, heart rate, arterial oxygen saturation) and the differences of the clinical indicators between the subgroups. Results The incidence of VAP in the observation group was significantly lower than that in the control group (P<0.05). The level of arterial oxygen saturation (SaO₂) of observation group were significantly higher than those of control group (all P<0.05). The ventilation time, ICU treatment time, systolic blood pressure, diastolic blood pressure, heart rate and the dosage of fentanyl, propofol and dexmedetomidine in observation group were significantly lower than those of control group (P<0.05). Conclusion According to the normal rest to adjust the use of sedative drugs can significantly reduce the incidence of adverse reactions and improve the level of clinical indicators of patients, which has high clinical value in the treatment of ICU patients with mechanical ventilation.