Post-lumbar puncture headaches (PLPHs) are a known complication of lumbar puncture procedures. Children undergoing treatment for cancer often undergo multiple lumbar punctures, placing them at increased risk for PLPHs. There are currently no guidelines for the prevention or management of PLPHs in children. A team was therefore assembled to conduct a systematic review of the evidence in relationship to PLPHs in the pediatric population. Clinical questions were developed and used to guide the literature review. Twenty-four articles were deemed appropriate for use and were evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Based on the review of evidence, strong recommendations are made for the use of smaller needle sizes and for the use of pencil point needles during lumbar puncture procedures. Weak recommendations are made for needle orientation and positioning following the procedure as well as for interventions used to treat PLPHs once they occur. There is a need for additional, pediatric-specific studies to further examine the issue of PLPH prevention and treatment.