The SARS-CoV-2 pandemic has affected 771 million people and caused 6.9 million confirmed deaths as of November 2023. Beyond the adversity, a crucial and less-explored chapter unfolds: adaptive sequelae. These have altered social, mental, and emotional conditions, leaving an imprint on biological systems. While some cases fully resolve the pathological process post-acute infection, others persist with symptoms, posing a challenge that underscores the need to comprehend pathophysiology from innovative perspectives. The article delves into “Long COVID” or Post-Acute COVID-19 Syndrome (PACS), where symptoms persist for ≥4 weeks irrespective of initial severity. Risk factors include a history of severe illness, in-hospital management, and intensive care. This article also explores theories, derived from various experimental models, that have demonstrated the involvement of the nervous system in coordination with the psychoneuroimmunoendocrine axes in the expression of inflammation. It is posited that PACS involves processes of peripheral and central sensitization (corticalization), facilitating dishomeostasis and the chronicity of the inflammatory process. In this context, various therapeutic strategies grounded in modulating the inflammatory reflex are reviewed, primarily through the infiltration of local anesthetics via linear and non-linear approaches. Neural therapeutic use is considered to stimulate the regulatory inflammatory circuits coordinated by the neuroimmune-endocrine system.