Background: The Port-A-Catheter is a reliable vascular access device used for long-term chemotherapy treatment at oncology centers. Recent research has shown that oncology nurses have inadequate knowledge and practice regarding Port-A-Catheter care. Therefore, improving nurses' knowledge and practice is crucial for compliance and minimizing complications. Using a simulation-based approach is one of the most effective methods of teaching because it enhances learning outcomes and nurses' performance. Aim: to evaluate the effect of a structured simulation-based training on oncology nurses' performance regarding Port-A-Catheter devices. Methods: A quasi-experimental design with one group pretest-posttest was utilized. A convenience sample was composed of 50 nurses in the oncology center at Mansoura University in Egypt. Tools: Port-A-Catheter Nurses' Knowledge Questionnaire and Accessing and De-Accessing Implanted Venous Port Checklist were used for data collection. Results: The total mean scores of nurses' knowledge regarding port-a-catheter were improved significantly immediately post- training and at follow-up, from 21.07 ±7.51 to 42.67 ±9.54 and 38.51 ±10.17, respectively. Moreover, the total mean practice scores post-training and at follow-up (141.57 ±17.09 and 136.51 ±23.99), respectively, were significantly higher than pre-training (76.92 ±29.35) (P < 0.001). Conclusion: The findings of the present study concluded that simulation-based training was an effective approach, improving nurses' knowledge and practice regarding Port-A-Catheter care. Recommendations: In-service training programs and continuing education are recommended for all staff nurses in different specialties, using simulation-based training to improve their attitude, knowledge, and performance regarding Port-A-Cath care.