Neurodegenerative diseases (NDs) pose a formidable challenge in modern healthcare and are characterized by progressive neuronal dysfunction and loss. Emerging research underscores the intricate interplay between neuroinflammation and mechanisms underlying ND pathogenesis. This review delves into the complex role of Krüppel-like factors (KLFs) in the context of neuroinflammation and major NDs. KLFs exert diverse effects in the brain on cellular processes such as blood-brain barrier integrity, neuronal cell cycle progression, and glial cell activation. Modulation of KLF expression and signaling emerges as a promising strategy to mitigate ND progression. By elucidating KLFs' multifaceted implications across diverse pathways and cellular processes implicated in ND progression, this review offers valuable insights into their therapeutic potential as targets for NDs.