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Objective To evaluate the efficacy and safety of emergency sclerotherapy for treating neonates with giant head and neck lymphatic malformations (LMs) complicated by airway obstruction. Methods This retrospective analysis included the clinical data of neonates with giant head and neck LMs complicated by airway obstruction treated at the Children's Hospital Affiliated to Shandong University from January 2020 to December 2024. All patients underwent emergency sclerotherapy under general anesthesia and real-time ultrasound guidance. After percutaneous puncture and pigtail drainage catheter placement, lesions were treated with alternating lavage with pingyangmycin and 1% lauromacrogol. Lesion volume was measured using three-dimensional (3D) volumetric MRI, and therapeutic efficacy was evaluated–3–6 months after the final treatment according to the volume reduction rate. Results A total of 13 neonates (8 males, 5 females) were enrolled in this study, with a mean birth weight of 3.47 ± 0.65 kg and a mean maximum lesion diameter of 9.42 ± 2.03 cm (range: 6.2–14.5 cm). There were seven cases of macrocystic LMs and six cases of mixed LMs, among which five lesions extended into the upper mediastinum and three had intralesional hemorrhage. A total of 57 sclerotherapy sessions were performed, with an average of 4.38 sessions per patient. The 3 neonates who underwent endotracheal intubation were successfully extubated 2–3 days after treatment. All patients achieved resolution of respiratory symptoms, with normal feeding and growth and no recurrence during follow-up. All 7 macrocystic LMs achieved excellent outcomes after a single sclerotherapy course. Among the six mixed LMs, four achieved excellent outcomes with one course, one required an additional sclerotherapy session, and one achieved excellent response after seven months of oral sirolimus. Transient low-grade fever (4 cases) and local swelling (7 cases) were observed as adverse reactions which resolved with symptomatic treatment, and no severe complications occurred. Conclusion Emergency sclerotherapy combined with indwelling drainage catheters is an effective and safe treatment for neonates with giant head and neck LMs complicated by airway obstruction. The alternating use of sclerosing agents, together with adjunctive sirolimus, enhances efficacy with minimal adverse reactions, offering greater therapeutic benefit than to single-agent therapy and significant clinical value.