Background: Mechanical ventilation is one of the most devices that are indispensable to use in Pediatric Intensive Care Units. However, all over the world many children are dying in Pediatric Intensive Care Units. Mechanical ventilation is help and supports management in the Intensive Care Unit, but it may cause a lot of threats and complications. This study aimed to evaluate the effect of a design nursing instruction on mechanically ventilated children in pediatric intensive care units. Methods: Research design: A quasi-experimental design was utilized to conduct this study. Settings: The study was convoyed at Pediatric Intensive Care Units at Suez Canal University Hospital and Ismailia Medical Center, Egypt. Sample: A convenient sample method of forty (40) nurses. Tools: The data was collected through a structured interview questionnaire sheet and observation to assess nurses' knowledge and practices of Mechanical ventilation. Results: There were statistically significant differences between the mean scores of the pre and post-test as regards nurses' knowledge and practices of mechanically ventilated children in Pediatric Intensive Care Units. Conclusions: Design nursing instruction has a positive outcome and improves nurses' practice regarding mechanically ventilated children's care. Recommendations: The current study recommended developing a written protocol for care of mechanically ventilated children and their clinical outcomes to support satisfactory knowledge, and competent practices are actually required in children's Intensive Care Units.