Objective: The management of central venous catheter (CVC) occlusion remains an area without clear evidence-based guidelines. Studies have been conducted that compare the use of heparin and normal saline for reducing thrombosis, but the evidence is not strong enough to suggest a significant advantage of one over the other. Therefore, the study aimed to assess the effectiveness of heparin and normal saline flushing in preventing CVC occlusion in pediatric patients with cancer. Data Sources: A comprehensive search was conducted in PubMed, Web of Science, Cochrane, MEDLINE, CINAHL, Embase, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov platform using specific keywords. The search was conducted until March 2022. Five randomized controlled trials are included in this study. Conclusion: Five studies with a total of 316 pediatric cancer patients met the inclusion criteria. The studies were found to be heterogeneous due to variations in the types of cancer, heparin concentration, flushing frequency of CVCs, and methods used to measure occlusion. Despite these differences, there was no significant difference in the effect of flushing with heparin and normal saline in preventing CVC occlusion. The analysis revealed that normal saline is as effective as heparin in preventing CVC occlusion among pediatric cancer patients. Implications for Nursing Practice: This systematic review and meta-analysis demonstrated that there is no significant difference between the use of heparin and normal saline flushing in preventing CVC occlusion among pediatric cancer patients. Considering the potential risks of heparin, the use of normal saline flushing may be recommended to prevent CVC obstruction.