Since the removal of codeine from hospital formularies, clinicians have increasingly turned to oral morphine to manage acute pain in children. However, recent evidence highlights a high prevalence of adverse effects and variable efficacy. Characterization of oral morphine pharmacokinetics and pharmacogenomics is necessary to guide the safe and effective use of oral morphine. We sought to explore the pharmacokinetics and pharmacogenomics of oral morphine in otherwise healthy children with fractures. We included a convenience sample of children age 5–17 years in the Paediatric Emergency Department with a deformed extremity fracture. Repeated blood samples were taken from an intravenous (IV) line for 120 minutes. Key pharmacokinetic parameters included time to maximum concentration (Tmax), peak serum concentration (Cmax), half-life, and area under the curve (AUC) for morphine and its metabolites: morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). Concentrations were determined by ultra performance liquid chromatography (UPLC) coupled to quadrupole time of flight (QTOF) mass spectrometry. Genotyping of single nucleotide polymorphisms (SNPs) was performed by TaqMan assay. Pain scores were collected using the Faces Pain Scale – Revised. We recruited 13 children (11 males) ranging from 4–16 (median 11.6) years. All participants received a single dose of oral morphine 0.5 mg/kg (maximum 20 mg). For morphine, M6G, and M3G, Tmax ranged from 30–120 minutes, 60–180 minutes, and 60–180 minutes, respectively; Cmax ranged from ranged from 6.2–52.6 ng/mL, 14.7–86 ng/mL, and 89.3–483.4 ng/mL, respectively; half-life ranged from 47.9–271.5 minutes, 71.2–400.5 minutes, and 94.7–278.3 minutes, respectively; AUC ranged from 250.1–6760.1 ng/mL*hr, 1129.4–9893.2 ng/mL*hr, and 8030.6–56246.5 ng/mL*hr, respectively. In one patient who reported no reduction from a pain score of 6, a SNP (RS563649) on the OPRMIgene locus previously shown to confer reduced receptor efficiency (less analgesia) was identified. In two patients, we identified a SNP (RS1799971) on the OPRMIgene locus previously shown to confer reduced metabolism, blood-brain barrier penetration, and receptor activity (less analgesia but fewer adverse effects). In 11 patients, we identified a SNP (RS1045642) on the ABCB1 gene locus previously shown to confer reduced intestinal p-glycoprotein expression (greater analgesia). Five patients were homozygous for a SNP (RS7439366) on the UGT2B7*2gene locus previously shown to confer reduced metabolism of M6G, an active metabolite (greater analgesia and nausea). Several SNPs confer variability in oral morphine’s pharmacokinetic and pharmacodynamic profile and may explain the wide variability in analgesic efficacy and adverse effects in children.