Abstract Background Enoxaparin is an anticoagulant used for pharmacologic thromboprophylaxis in pediatrics. Enoxaparin pharmacokinetics can be altered in the setting of obesity. Optimal enoxaparin dosing for thromboprophylaxis in children with obesity remains unclear. Procedure A retrospective review was conducted of pediatric patients who weighed ≥60 kg with BMI ≥ 95th percentile, received enoxaparin for thromboprophylaxis, and had at least one appropriately drawn anti‐factor Xa (anti‐Xa) from 2013 to 2022. Anti‐Xa levels were reviewed for patients initially treated with enoxaparin 30 mg every 12 h. The average daily enoxaparin dose required to achieve an anti‐Xa of 0.2–0.4 unit/mL, which was stratified by BMI percentile and weight, was calculated. Results Of 116 patients (median age 15.8 years) included for analysis, 106 patients were initially treated with enoxaparin 30 mg every 12 h. Anti‐Xa levels were <0.2 unit/mL in 53% of patients with BMI > 99th percentile and 54% of patients >100 kg. Ninety‐one patients had at least one anti‐Xa 0.2–0.4 unit/mL with an average daily enoxaparin dosing of 66 mg. When stratified by severity of obesity, higher doses were required to attain an anti‐Xa 0.2–0.4 unit/mL in patients with BMI > 99th percentile compared with those with 95th–99th percentile (67.8 ± 15.7 vs. 62 ± 5.6 mg/day, p = .01). Patients > 100 kg required significantly higher dose than those ≤100 kg (69.1 ± 15.5 vs 61.2 ± 7.3 mg/day, p = .002). Conclusions Increased initial dosing and/or anti‐Xa level monitoring should be considered in adolescents with severe obesity receiving enoxaparin thromboprophylaxis.