Purpose <p>To evaluate the clinical efficacy and safety of ultrasound-guided sclerotherapy for macrocystic and mixed head and neck lymphatic malformation (LM) in neonates and young infants, and to compare the outcomes of Pingyangmycin versus OK-432 while exploring the impact of intervention timing on prognosis.</p> Methods <p>A retrospective historical cohort study was conducted on 30 infants (age ≤ 90 days) with head and neck LM treated between 2018 and 2024. In adherence to the STROBE statement, we report the study design and findings. Patients were categorized into an earlier OK-432 group (<i>n</i> = 14) and a later Pingyangmycin group (<i>n</i> = 16). Subgroup analysis was performed by stratifying patients into a neonatal group (≤ 28 days) and a young infant group (29–90 days).</p> Results <p>The overall clinical cure rate was 96.7%. (1) Impact of Age: The single-session cure rate was numerically higher in neonates than in young infants (85.7% vs. 56.3%), demonstrating a favorable clinical trend despite the limited sample size (<i>P</i> = 0.12 by Fisher’s exact test). (2) Sclerosing Agents: Clinical cure rates were comparable between the Pingyangmycin (100%) and OK-432 (92.9%) groups (<i>P</i> = 0.47). However, regarding safety, the Pingyangmycin group exhibited a lower incidence of adverse events compared to the OK-432 group (6.3% vs. 28.6%, <i>P</i> = 0.15). Severe inflammatory responses occurred only in the OK-432 group. No major acute or long-term complications, such as anaphylaxis, pulmonary fibrosis, or nerve injury, occurred in any patient.</p> Conclusion <p>Ultrasound-guided sclerotherapy is highly effective for head and neck LM in infants aged ≤ 90 days. Neonatal intervention yields a favorable trend toward single-session efficacy. Compared with OK-432, Pingyangmycin demonstrates a more favorable safety profile, suggesting it as a promising alternative sclerosing agent for this specific population.</p>