Background: Protective lung strategies (PLS) are guidelines about recent clinical advances that deliver an air volume compatible with the patient’s lung capacity and are used to treat acute respiratory distress syndrome. These mechanical ventilation guidelines are not implemented within intensive care units (ICUs) despite strong evidence-based recommendations and a dedicated professional staff. Nurses’ familiarity with clinical guidelines can bridge the gap between actual and recommended practice. However, several barriers undermine this process. The objectives of this study were to identify those barriers and explore the knowledge, attitudes, and behavior of ICU nurses regarding the implementation of PLS. Methods: This was a descriptive, cross-sectional study. The participants were nurses working in the six ICUs of a pediatric tertiary care hospital in Lahore, Pakistan. Using purposive sampling with random selection, the total sample size was 137 nurses. A summative rating scale was used to identify barriers to the implementation of PLS. Results: Overall, the nurses’ barrier score was high, with a mean of 66.77±5.36. Across all the barriers subscales, attitude was a much more significant barrier (35.74±3.57) to PLS than behavior (6.53±1.96), perceived knowledge (17.42±2.54), and organizational barriers (7.08±1.39). Knowledge-related barriers were also significantly high. Conclusion This study identified important barriers to PLS implementation by nurses, including attitudes and knowledge deficits. Understanding those barriers and planning interventions to address them could help to increase adherence to low tidal volume ventilation and improve patient outcomes. Nurses’ involvement in mechanical ventilation management could help to safely deliver air volumes compatible with recommendations.