Background: The evidence shows a reduction in pediatric emergency department (PED) flows during the early stages of the COVID-19 pandemic. Using interrupted time-series analysis, we evaluated the impact of different stages of the pandemic response on overall and cause-specific PED attendance at a tertiary hospital in south Italy. Our methods included evaluations of total visits, hospitalizations, accesses for critical illnesses and four etiological categories (transmissible and non-transmissible infectious diseases, trauma and mental-health) during March–December 2020, which were compared with analogous intervals from 2016 to 2019; the pandemic period was divided into three segments: the “first lockdown” (FL, 9 March–3 May), the “post-lockdown” (PL, 4 May–6 November) and the “second lockdown” (SL, 7 November–31 December). Our results showed that attendance dropped by a mean of 50.09% during the pandemic stages, while hospitalizations increased. Critical illnesses decreased during FL (incidence rate ratio -IRR- 0.37, 95% CI 0.13, 0.88) e SL (IRR 0.09, 95% CI 0.01, 0.74) and transmissible disease related visits reduced more markedly and persistently (FL: IRR 0.18, 95% CI 0.14, 0.24; PL: IRR 0.20, 95% CI 0.13, 0.31, SL: IRR 0.17, 95% CI 0.10, 0.29). Non-infectious diseases returned to pre-COVID-19 pandemic levels by PL. We concluded that that the results highlight the specific effect of the late 2020 containment measures on transmissible infectious diseases and their burden on pediatric emergency resources. This evidence can inform resource allocation and interventions to mitigate the impact of infectious diseases on pediatric populations and the health-care system.