<p>Nobiletin (NOB), a naturally occurring polymethoxyflavonoid, has been shown to regulate the expression of the clock gene BMAL1. This study aims to explore the impact of NOB nanoparticles on microglial polarization and cognitive impairments resulting from chronic sleep paradoxical deprivation (PSD), as well as the mechanisms involved. Following PSD modeling, rats treated with NOB nanoparticles exhibited significantly improved cognitive performance in behavioral tests. The treatment upregulated the expression of BMAL1, SIRT1, E2F1, and the NAD+/NADH ratio, shifted microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, and enhanced antioxidant defenses. The NAD⁺ inhibitor apocynin and silencing of BMAL1 could reverse the effects of NOB nanoparticles. Overexpression of BMAL1 had similar effects to NOB nanoparticles in LPS-induced cellular models, while silencing of SIRT1 or E2F1 reversed the effects. Co-immunoprecipitation experiments illustrated the binding of SIRT1 and BMAL1 and SIRT1 and E2F1. NOB nanoparticles alleviate chronic PSD-induced microglia M1 polarisation, inflammation, and cognitive deficits in rats by a mechanism that may be related to the BMAL1/SIRT1/E2F1 axis, providing a new direction for the therapeutic approach of chronic PSD-associated cognitive deficits.</p><p></p>