Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti-oxidative stress and anti-inflammation properties; however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine-specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro-inflammatory TNFR1/NF-κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti-inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPs@FMN) is established, which penetrated the blood brain barrier with enhanced microglial-targeted delivery efficiency. Notably, MNPs@FMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide-induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimer's disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation-dependent cognitive decline.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.