Up to 20% of orthopedic surgeons still avoid the use of cephalosporins in patients with penicillin allergies despite its reported safety in the adult and general surgery pediatric population. The primary objective is to determine the incidence of adverse effects and allergic reactions when using cephalosporins in pediatric orthopedic patients labeled as penicillin-allergic as compared to those without previously reported penicillin allergy. A multicenter retrospective chart review was performed across three level 1 trauma centers from January 2013 to February 2020 to identify penicillin-allergic as well as non-penicillin-allergic pediatric patients treated for orthopedic injuries. Data were collected regarding patient demographics, antibiotic administered, timing of antibiotic administration, reported drug allergy, and described allergic reaction. Postoperative or intraoperative allergic reactions to antibiotics, surgical site infections, and complications were recorded. A total of 2289 surgeries performed by four fellowship-trained surgeons were evaluated. Eighty-five patients diagnosed with penicillin allergy were identified and underwent 95 surgeries and 95 patients without previously reported penicillin allergy underwent 95 surgeries. One patient, with a documented history of anaphylaxis to cefazolin, sustained an anaphylactic reaction intraoperatively to cefazolin. There were no other reported reactions, surgical site infections, or complications. There was no statistically significant difference in rate of allergic reaction in patients with previously reported penicillin allergy treated with cefazolin and those with no previous reported reaction (P > 0.05). Prophylaxis with cephalosporins is not associated with increased risk for allergic reaction. Cephalosporins can be safely administered to pediatric patients with penicillin allergy undergoing orthopedic intervention. Level of evidence: Level II, Multicenter Retrospective Prognostic Study.