Background: Mechanical ventilation is life-saving handling to the maintenance of patients throughout oxygenation and ventilation. Critical care nurses have the most crucial role among health care workers in the skillful handling of mechanically ventilated patients.  So, nurses must have the awareness, skills, and capabilities to handle a patient receiving mechanical ventilation adequately.  Aim: to assess the effectiveness of the in-service training module on intensive care nurses' performance regarding mechanical ventilator patients' skillful handling. Design: A quasi-experimental design was used. Setting: The study was conducted at intensive care units affiliated with 3 Public Hospitals related to the Ministry of Health. Subjects: A purposive sample of 60 nurses who worked in the previously mentioned setting. Data collection tools: Nurses' structured self-administered questionnaire and nurses' practical skill competency checklist. Results: The study shows that (85% & 80%) of the studied nurses gained a higher retained level of knowledge and practice in the follow-up phase compared with (31.7% & 35%) in the pre-test phase. Conclusion: The majority of studied nurses get promoting the achievement of nurses' knowledge level and enhancement of nurses' practice level with a highly statistically significant positive correlation between cumulative total knowledge and practice regarding care of mechanically ventilated patients during pre, post & three months follow-up phases at (r= 0.987 and P= 0.000). Recommendations: Develop ongoing in-service training courses on mechanically ventilated patient care which should be mandatory for newly employed nurses. Emerging a regular rating determines nurses' training requirements for updating nurses' knowledge and practice.