Background Most children with trisomy 13 display central apnea, and are prone to opioid-induced respiratory depression. We conducted opioid-free anesthesia for a patient with trisomy 13 and obstructive sleep apnea, and safely extubated the patient in the operating room. Case presentation A 27-month-old girl with trisomy 13 underwent tonsillectomy. Given her high sensitivity to opioids, general anesthesia was introduced and maintained only with 2–5% sevoflurane and 33% nitrous oxide in oxygen. We used acetaminophen for postoperative analgesia. The tracheal tube was removed under stable breathing pattern 10 min after the surgery in the operating room. Two years later, opioid-free anesthesia with 2–5% sevoflurane and 33% nitrous oxide in oxygen was again performed safely for tube insertion into both eardrums. Conclusion Opioid-free anesthesia with adequate non-narcotic analgesics is safe for children with trisomy 13 with multiple apnea-related comorbidities.