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• Cellular senescence and resistance to apoptosis are observed in Astrocytes during cerebral malaria in mice and humans. • Astrocyte senescence is triggered by LC3-dependent non-conventional autophagy when interacting with the malaria parasite. • Parasite-induced senescence promotes the production of CX-CL10 by astrocytes. • Treatment with senolytic drugs prevents CM by reducing the inflammatory response. Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms that contributes to neuroinflammation in CM. By studying a mouse model of CM (caused by P. berghei ANKA), we describe that the induction of autophagy promoted p21-dependent senescence in astrocytes and that CXCL-10 was part of the senescence-associated secretory phenotype. Furthermore, p21 expression was observed in post-mortem brain and peripheral blood samples from patients with CM. Lastly, we found that the depletion of senescent astrocytes with senolytic drugs abrogated inflammation and protected mice from CM. Our data provide evidence for a novel mechanism through which astrocytes could be involved in the neuropathophysiology of CM. p21 gene expression in blood cell and an elevated plasma CXCL-10 concentration could be valuable biomarkers of CM in humans. In the end, we believe senolytic drugs shall open up new avenues to develop newer treatment options. [ABSTRACT FROM AUTHOR]