Background: This study aimed to evaluate Emergency Department and Intensive Care Unit nurses’ skills in interpreting blood gas analysis results and to use those interpretations in clinical decision-making. Methods: In this prospective, multicenter, simulation-based study, nurses from the Emergency Department (ED) of Merano Hospital and the Intensive Care Unit (ICU) of Bolzano Hospital, Italy, were presented with 16 clinical vignettes based on real patient cases. These vignettes were designed to evaluate the nurses’ ability to identify patients with time-dependent conditions and recommend appropriate therapeutic interventions. Outcomes measured included sensitivity, specificity, and agreement with physician-assigned urgency levels and therapy recommendations. Results: Among the 43 participants (26 ICU and 17 ED nurses), specificity in excluding patients without time-dependent conditions or organ replacement needs was high. However, sensitivity in identifying time-dependent conditions was less than 50%. Agreement with physician-assigned urgency levels was low, with Cohen’s kappa values of 0.139 for ICU nurses and 0.218 for ED nurses. Nurses with lower self-confidence in interpreting BGA results made more errors, while other personal or professional factors did not significantly impact performance. Conclusions: Although critical care nurses can effectively rule out patients without time-dependent conditions, their ability to identify such conditions requires improvement. These findings underscore the need for targeted training programs to enhance nurses’ BGA interpretation skills and clinical decision-making in high-pressure, time-sensitive situations.