This study evaluated the clinical effectiveness of comprehensive nursing intervention in preventing ventilator-associated pneumonia (VAP). A total of 116 mechanically ventilated patients admitted between June 2018 and December 2019 were randomly assigned to a control group (conventional nursing, n=58) or an observation group (comprehensive nursing, n=58). Outcome measures included duration of mechanical ventilation, length of hospital stay, VAP incidence, psychological status, quality of life, and nursing satisfaction. Patients receiving comprehensive nursing demonstrated significantly shorter ventilation and hospitalization periods compared to the control group (P<0.05). The incidence of VAP was notably lower in the observation group (3.44% vs. 13.79%, P<0.05). Post-intervention assessments using the Self-Rating Anxiety Scale and Self-Rating Depression Scale indicated significantly better psychological outcomes in the observation group (P<0.05). Additionally, quality of life scores improved more substantially, and nursing satisfaction rates were higher (94.87% vs. 81.03%, P<0.05). These findings highlight the critical role of comprehensive nursing in enhancing both physical and psychological outcomes while effectively reducing VAP risk in mechanically ventilated patients.