Background The use of procedural sedation and analgesia for painful procedures in children with hematological malignancies has become a standard practice in recent time. We compared the occurrence of hypoxia, apnea, and pain between ketamine–propofol and ketamine–midazolam combination. Patients and methods This randomized, open-labeled cross-over study was conducted in 60 children aged 1–15 years scheduled for bone marrow aspiration and, or intrathecal chemotherapy. They were divided into two groups of 30 to receive either ketamine–propofol or ketamine–midazolam. Sedation was performed by trained anesthetists according to the study protocol. Data were analyzed with independent t-test, χ2-test and Fisher’s exact test. P value 0.05 or less was considered significant. Results A total of 120 procedures were performed. One (1.7%) patient in each group had hypoxia, (P=0.8). The oxygen saturation decreased to 83 and 88% in ketamine–propofol and ketamine–midazolam groups, respectively. This was accompanied by bradycardia with a heart rate of 56 and 58 beats/min, respectively. Both events responded to oxygen therapy. There was no episode of apnea, and all maintained spontaneous respiration. The number of patients with a pain score of at least 5 during the procedure was comparable; ketamine–propofol group [6 (10%)] versus ketamine–midazolam group [4 (6.7%)] (P=0.4). Hallucinations were more common in the ketamine–propofol group [4(6.7%)] than the ketamine–midazolam group [0 (0%)] (P=0.05). Conclusion The occurrence of hypoxia, apnea, and pain was comparable following the administration of ketamine–propofol and ketamine–midazolam combination.