Pediatric thrombocytopenia, particularly immune thrombocytopenic purpura (ITP), poses a significant bleeding risk, necessitating effective treatment options. Traditional therapies such as corticosteroids and intravenous immunoglobulin (IVIG) are associated with adverse effects and limited long-term efficacy. This randomized controlled trial evaluates the efficacy and safety of thrombopoietin receptor agonists (TPO-RAs) and monoclonal antibodies compared to corticosteroids in pediatric patients with chronic thrombocytopenia. A total of 120 children aged 2–16 years with chronic ITP or secondary thrombocytopenia were randomized into three groups: TPO-RAs (eltrombopag or romiplostim), monoclonal antibodies (avatrombopag or anti-CD40L), and corticosteroids (prednisolone). The primary outcome was achieving a platelet count ≥100,000/µL at 12 weeks, with secondary outcomes including bleeding episodes, quality of life (PedsQL), adverse events, and remission duration. Keywords: Pediatric At 12 weeks, mean platelet counts were significantly higher in the TPO-RA (120,000/µL) and monoclonal antibody (115,000/µL) groups than in the corticosteroid group (45,000/µL) (p<0.01). Bleeding episodes were significantly lower in the novel therapy groups (p<0.05), and quality of life improved more substantially (p<0.05). Adverse events were fewer in the TPO-RA and monoclonal antibody groups, while corticosteroid-treated patients experienced significant side effects. Remission persisted in 55% of patients in the novel therapy groups versus 20% in the corticosteroid group at six months (p<0.01). This study demonstrates that TPO-RAs and monoclonal antibodies are effective and safe alternatives to corticosteroids in pediatric thrombocytopenia, offering superior platelet count restoration, reduced bleeding risk, and prolonged remission.