SARS-Cov-2 infections have claimed nearly 7 million lives worldwide since 2019. While quarantines, non-pharmaceutical mandates and antiviral vaccines have diminished the transmission and severity of infections, many victims recovering from acute COVID-19 have had lingering symptoms or have an onset weeks or months later. This is known as Long COVID or Post-acute sequelae of COVID-19 (PASC). PASC is a multi-organ syndrome with many dysfunctions described therefrom (reviewed in Davis et al., 2023). Most prominent and debilitating are symptoms of cognitive impairment – mental focus, disordered sleep, memory loss and general fatigue. Plausible biological explanations for PASC are few and there is a lack of efficacious therapies. The present review provides laboratory evidence invoking the critical role of cholinergic mechanisms mediated by ubiquitous α7 nicotinic acetylcholine receptors (α7 nAChRs) whose dysfunctions and impairments appear to link to the etiology for PASC and may provide therapeutic avenues for PASC.