Background: Oxygen is necessary for life to exist particularly for patients who are undergoing cardio- thoracic surgery; the cardiac surgery is impossible without a continuous oxygen therapy in order to improvement of all the treatment stages Aim: The study aimed to explore the effect of protocol of care regarding oxygen therapy for patients after cardiac and thoracic surgery on nurse's knowledge. Subjects and method: Research design: a quasi-experimental study design was used. Setting: The investigation was conducted at the critical care units of three hospitals in Port-Said, Egypt—Al-Shifa Medical Complex, Alsalam Hospital, and Alzohor Hospital—all of which are part of the Egypt Health Care Authority. Sample: 50 nurses who worked in postoperative cardiac and thoracic surgery units and intensive care units, Tools of data collection: the Nurses' Knowledge Questionnaire. Results: The present research found that prior putting the care protocol into place, the studied nurses' understanding levels regarding oxygen therapy for patients following heart and thoracic surgery were low. While, there was also an enhancement in the overall scores of the studied nurses' understanding and expertise regarding oxygen therapy for patients following cardiac and thoracic surgery after implementation of the protocol of. Conclusion: The care regimen was successful in improving the nurses' understanding of oxygen therapy for patients following heart and thoracic surgery. Recommendations: ongoing education and training sessions to ensure the safe delivery of oxygen therapy and the provision of high-quality medical care to patients on oxygen therapy.