Oral propranolol is the first-line therapy for infantile hemangioma (IH), but its mechanism of action remains unclear. The aim of this study was to evaluate the change in serum vascular endothelial growth factor (VEGF) levels in patients with IH who underwent propranolol treatment. The study included 22 patients with IH receiving propranolol treatment. At three time points—before treatment and 1 and 3 months after treatment—blood samples were examined by enzyme-linked immunosorbent assay for serum VEGF expression. The mean serum VEGF concentration in children with proliferative hemangiomas was 395.0 ± 176.7 pg/mL, approximately twice as high as in patients with venous malformations (mean 170.7 pg/mL) and in healthy controls (204.8 pg/mL, p = 0.006). After 1 month of propranolol treatment, the level had fallen 21.6% (p = 0.003), although the downward trend was less obvious after 3 months of treatment (18.0%, p = 0.63). VEGF expression correlated significantly with the lesion size (correlation coefficient [R] = 0.43, p = 0.046), whereas no correlation was observed with age (R = 0.13, p = 0.56). Serum VEGF levels were higher in patients with IH and fell after 1 month of oral propranolol treatment. Similar results, although less pronounced, were found after 3 months of treatment. Lesion volume and serum level of VEGF were significantly correlated.