Objective To explore the effect of using cluster nursing measures on expectoration in mechanical ventilation patients after craniocerebral operation. Methods Convenient sampling and controlled trials at not the same period were used. Sixty-seven mechanical ventilation patients after craniocerebral operation were selected as the research objects in Department of Neurosurgery Intensive Care Unit (ICU) of the First Hospital Affiliated to Wenzhou Medical College. Thirty-two patients treated from June 2015 to June 2016 were assigned in the control group, and they were given routine respiratory nursing care; 35 patients admitted and treated from July 2006 to July 2017 were included in the intervention group, and they were given evidence-based cluster nursing intervention measures on the basis of routine care. The differences in expectoration effect, arterial blood gas analysis index, incidence of pulmonary infection and prognosis of patients in two groups were compared. Results Compared with control group, the amount of expectoration in the intervention group was significantly increased (mL/d: 49.69±9.45 vs. 33.72±10.63, P < 0.05), while the daily number of sputum suction (times: 21.57±2.31 vs. 28.76±22.66), the time needed for each sputum suction(s: 6.81±1.74 vs. 9.28±2.52), respiratory frequency (bpm: 26.26±1.83 vs. 28.58±1.36), incidence of pulmonary infection [0 vs. 12.5% (4/32)], time of mechanical ventilation (days: 6.37±2.51 vs. 8.92±3.32), time of ICU stay (days: 7.49±3.87 vs. 10.33±2.12), time of hospital stay (days: 10.31±1.99 vs. 14.56±3.57), fatality rate [8.6% (3/35) vs. 21.9% (7/32)] in the intervention group were significantly decreased (all P < 0.05); after treatment the arterial partial pressure of oxygen (PaO2) and pulse oxygen saturation degree (SpO2) were significantly increased than those before treatment, and the arterial partial pressure of carbon dioxide (PaCO2) was significantly decreased than that before treatment, and the degrees of improvement in the intervention group on 5 days were significantly better than those in the control group [PaO2(mmHg, 1 mmHg = 0.133 kPa): 60.89±3.44 vs. 57.34±2.49, PaCO2(mmHg): 41.06±4.32 vs. 45.22±4.78, SpO2: 0.986±0.030 vs. 0.963±0.023, all P < 0.05]. Conclusion The cluster nursing measures can effectively improve the expectoration effect for mechanical ventilation patients after craniocerebral surgery, reduce the mortality and incidence of pulmonary infection, shorten the stay in ICU and improve the prognosis, suggesting that the measures be worthy to be applied widely in clinics.