Antimicrobial prophylaxis (AMP) is recommended preoperatively for “clean” spinal and cranial operations, but the amount and timing are still up for debate. In the pediatric context, using multiple-dose AMP for such procedures is debatable. The authors of this clinical trial wanted to assess single-dose versus multiple-dose prophylactic antibiotic use in pediatric patients undergoing cranial and spinal neurosurgical procedures. The sample consisted of 300 age and sex-matched patients and was evenly dispersed over 3 bi-arm cohorts. There was no statistically significant intercohort difference in etiology or operation type (p < 0.05). The total cohort (adjusted OR 0.65, 95% CI 0.27–1.57), as well as each of the subcohorts (non-instrumented clean spinal, adjusted OR 0.65, 95% CI 0.12–3.44; non-instrumented cranial, adjusted OR 0.52, 95% CI 0.14–2.73; and instrumented cranial, adjusted OR 0.68, 95% CI 0.13–3.31), yielded nondiscriminating results. In pediatric neurosurgical scenarios, there was no substantial benefit for multiple-dose AMPs over single-dose AMPs. Single-dose AMP appears to be the best option.