Background <p>To evaluate targeted therapy for Langerhans cell histiocytosis (LCH) with maxillofacial manifestations, we conducted a retrospective study of 20 children admitted from January 2016 to June 2021.</p> Methods <p>The maxillofacial LCH exhibited diverse clinical features and laboratory indices. Seventeen patients were refractory to standard treatments, and three patients directly underwent targeted therapy. Sixteen patients with <i>BRAF</i>^<i>V600E</i> mutation were treated with dabrafenib, and four patients with <i>MAP2K1</i> mutation were treated with trametinib.</p> Results <p>The cohort included nine males and eleven females, with a median 0.92 years at diagnosis and 1.70 years at initiation of targeted therapy. Three patients had single-system LCH and 17 patients had multi-system LCH. Lesions affected the mandibular bone in 17 patients, the temporal bone in 12 patients, and the maxilla in 10 patients. Ki-67 expression before targeted therapy correlates with maxillary involvement (coefficient 0.61; <i>P</i> &lt; 0.05). The <i>cfBRAF</i>^<i>V600E</i> level after first month of targeted therapy was significantly lower than before targeted therapy (<i>P</i> &lt; 0.001). After a median 18 months of targeted therapy and 22 months of follow-up, 17 patients achieved complete remission, and 3 patients achieved partial remission. The objective response rate was 65%, and the disease control rate was 100%. Five patients experienced progression or reactivation, and ten patients had skin rashes.</p> Conclusion <p>Overall, targeted therapy demonstrated good efficacy with mild tolerable adverse events.</p>