Neurodegenerative diseases represent a significant and escalating global health challenge, with no curative therapies currently available. Among the converging cellular and molecular mechanisms implicated in neurodegeneration, chronic neuroinflammation and impaired autophagy constitute a pathogenic feedback loop that accelerates proteostatic disruption, mitochondrial dysfunction, and synaptic degeneration. This chapter critically examines current evidence elucidating how microglial and astrocytic inflammatory signaling pathways, predominantly nuclear factor kappa B (NF-κB) and NLRP3 inflammasome activation, impair autophagic flux through key regulatory nodes, including mTORC1 hyperactivation, suppression of Beclin-1, and lysosomal membrane destabilization. In turn, autophagy failure exacerbates neuroinflammatory responses by endorsing the accumulation of dysfunctional organelles and protein aggregates. In addition, disease-specific patterns are explored, with emphasis on amyloid-β-driven pathology in Alzheimer’s disease, α-synuclein propagation in Parkinson’s disease, and TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal dementia. Finally, we discuss emerging therapeutic strategies that combine autophagy-enhancing agents with anti-inflammatory interventions, including advanced drug delivery platforms capable of crossing the blood–brain barrier. By explaining the bidirectional interplay between autophagy and neuroinflammation, this chapter provides a mechanistic framework for the rational design of targeted therapies aimed at interrupting the self-amplifying cycles that drive neurodegeneration.