Background: Thrombopoietin receptor agonists (TPO-RAs) have demonstrated efficacy in treating clinically significant thrombocytopenia, including chemotherapy-induced thrombocytopenia (CIT) in adults. However, data regarding their safety and efficacy in pediatric, adolescents, and young adult (AYA) patients with hematologic malignancies are limited. Methods: We retrospectively identified 15 pediatric and AYA patients aged 25 years or younger with hematologic malignancies treated with a TPO-RA at UCSF Benioff Children’s Hospitals between 2015 and 2023. Platelet counts and transfusion requirements were compared before and after TPO-RA therapy. Results: The median age at TPO-RA initiation was 16 years (range: 7-25 years). Nine patients (60%) had a history of bleeding or comorbidity that predisposed to severe bleeding risk. Eleven patients received romiplostim and four patients received eltrombopag. The median platelet count significantly increased from 24 x 10 ⁹/L at baseline to 54 x 10 ⁹/L after 3 weeks of any TPO-RA therapy (p =0.029). Monthly platelet transfusion requirements significantly decreased from a median of 15 to two units after TPO-RA therapy (p=0.007). Fourteen of the 15 patients (93%) achieved a sustained platelet count >50,000/µL within eight weeks, with a median time to response of 3 weeks. No TPO-RA-related adverse events were observed. Conclusion: TPO-RAs were effective in managing refractory thrombocytopenia in pediatric and young adult patients being treated for hematologic malignancies, with a favorable safety profile, even among patients with multiple comorbidities. These findings warrant further investigation through prospective clinical trials to confirm efficacy and establish clinical guidelines for this population.