COVID-19 impacted the entire world’s population, frequently resulting in long-lasting neuropsychiatric complications. Furthermore, social distancing, lockdowns and fear for one’s personal health worsen individual psychological wellbeing, especially in children and adolescents. Herein, we discuss the results of studies that specifically reported data about the impact of the COVID-19 pandemic or infection on children with Pediatric Acute-Onset Neuropsychiatric Disorders (PANS). Furthermore, we present the cases of five adolescents with PANS whose symptomatology increased following SARS-CoV-2 infection. What emerged from this study was that COVID-19 resulted in the exacerbation of obsessions, tics, anxiety and mood symptoms and decreased wellbeing. Moreover, new symptoms, as well as new PANS cases, are reported to have arisen after COVID-19 infection. Here, we hypothesize that the pathogenic mechanisms of silent viruses, such as the Epstein–Barr virus, are related to neuroinflammation, immune responses and reactivation, with additional roles played by social-isolation-related inflammatory processes. The discussion of PANS, which represents a model of immune-mediated neuropsychiatric manifestations, is particularly relevant, with the aim of uncovering the mechanisms that lead to neuropsychiatric Post-Acute COVID-19 Syndrome (PACS). Prospects for future studies and treatment implications are discussed.