Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and neurotoxic reactive astrocytes are gaining recognition for their pivotal roles in the progression of neurodegenerative diseases. RIPK1, a key regulator of necroptosis and inflammation, interacts with astrocytes to exacerbate neuroinflammation and neuronal damage. Neurotoxic reactive astrocytes, often induced by inflammatory microglia, contribute to synaptic dysfunction and neuronal death, further advancing disease pathology. This review highlights the mechanisms underlying RIPK1-mediated signaling and the generation of reactive astrocytes, emphasizing their interplay in neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Understanding these pathways offers new opportunities for targeted therapeutic strategies to mitigate neurodegeneration.