Neuroinflammation refers to the complex innate immune response mediated by various neuroglial cells in the central nervous system in response to infections, injuries, toxic metabolites, or autoimmune conditions (Yang and Zhou, Glia 67:1017–1035, 2019). Studies have shown that neuroinflammation is one of the most common pathologies in various neurological diseases, including neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and various central nervous system injuries (Becher et al., Nat Rev Immunol 17:49–59, 2017). In recent years, neuroinflammation has emerged as a hot topic in neuroimmunology and neurodegeneration research, with numerous studies revealing that targeted regulation of neuroinflammation is crucial for the treatment of neurological diseases. Nicotinamide adenine dinucleotide phosphate (NADPH), also known as reduced coenzyme II, plays a crucial role as a hydrogen supplier in many biochemical reactions in the body, contributing to the maintenance of cellular redox homeostasis (Fan et al., Nature 510:298–302, 2014). There is ample evidence indicating that NADPH is involved in regulating the pathological processes of neuroinflammation. However, intriguingly, NADPH often exhibits a dual role in mediating neuroinflammation. On the one hand, as a hydrogen donor, NADPH participates in various intracellular reduction reactions, such as the generation of reduced glutathione (GSH), thereby combating oxidative damage from reactive oxygen species (ROS) and resisting inflammation (Stanton, IUBMB Life 64:362–369, 2012). On the other hand, as a substrate for the NADPH oxidase (NOX) family, NADPH provides electrons for ROS generation, serving as an important mechanism for NADPH involvement in inflammatory signaling (Cui et al., Redox Biol 26:101295, 2019). This section will focus on elucidating the mechanisms by which NADPH mediates anti-inflammation and neuroinflammation and its significance in the pathogenesis of neurological diseases.