Parkinson's disease (PD) is a common neurodegenerative disorder whose pathogenesis is complex and remains incompletely understood. Oligomers formed by the abnormal aggregation of α‍-synuclein (α‍-syn) are considered one of the central culprits of PD pathology. These oligomers accumulate not only within neurons but also propagate pathological changes by mediating neuron-glia crosstalk. Accumulating evidence indicates that α‍-syn oligomers exacerbate neuronal injury and accelerate neurodegeneration by triggering glial activation and inflammatory responses. Nevertheless, the precise molecular mechanisms through which α-syn oligomers transduce signals between neurons and glia are still largely unresolved. Here we systematically review the biogenesis and toxic mechanisms of α-syn oligomers, the activation states of glial cells and their associated inflammatory pathways, and the latest advances in intercellular signaling between the two compartments, with the goal of illuminating the pivotal roles of these processes in PD pathobiology. By integrating these molecular insights, we aim to provide new theoretical frameworks and research directions for the early diagnosis and treatment of Parkinson's disease, thereby fostering the development of innovative therapeutic strategies.