Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are driven by intertwined pathological mechanisms. Since traditional therapeutic strategies targeting single pathways have limited clinical success, this chapter underscores the necessity of dual-target approaches that simultaneously modulate neuroinflammatory cascades and restore autophagic flux to halt disease progression. By dissecting the mechanistic crosstalk between inflammasome activation and autophagic failure, this chapter provides a roadmap for developing advanced therapeutics. It critically evaluates current strategies, including small-molecule inhibitors, biologic agents, and emerging multimodal interventions such as nanoparticle-based drug delivery, gene therapies, and repurposed drugs. This chapter also addresses translational challenges like blood–brain barrier penetration, off-target effects, and combinatorial therapy optimization while highlighting preclinical and clinical advancements. The urgency of this dual targeting is underscored by the limitations of monotherapies in addressing the multifactorial nature of diseases. Chronic neuroinflammation exacerbates autophagy impairment by creating a self-sustaining cycle of neuronal damage, whereas defective autophagy amplifies inflammatory signaling through protein aggregate accumulation. Next, it also advocates personalized, multimodal regimens tailored to disease-specific neuroinflammatory and autophagy signatures, emphasizing the need for biomarker development and ethical considerations in gene-editing trials.