Microglia, resident macrophages that act as the brain’s innate immune cells, play a key role in initiating a defense response to the infection or neuroinflammation of the host. Once a broad spectrum of dangers is confronted, microglia get triggered and transform their role against immune stimuli. Recent studies have shown that remarkable metabolic changes present in activated microglia affect their immune function. Given that the important role of microglia in the progression of neurodegeneration is widely recognized, it is crucial to know whether metabolic reprogramming of microglia also presents in neurodegeneration and how this may influence their role in neurodegeneration progression. This paper provides an overview of the metabolic reprogramming of microglia, the major pathways involved in recent advances in five major neurodegenerative diseases of aging (NDAs), including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), etc. And then we elucidated their impacts on the disease progression of neurodegeneration. Furthermore, growing evidence suggests that microbiota-derived metabolites, including acetate, N⁶-carboxymethyllysine (CML), and isoamylamine (IAA), regulate metabolic pathways and functions of microglia, and play a crucial role in cellular homeostasis. We shed light on this topic and concluded these metabolites are potential therapeutic targets for NDAs.