AbstractAstrocytes are glial cells that help maintain brain homeostasis and become reactive in neurodegenerative processes releasing both harmful and beneficial factors. We have demonstrated that brain‐derived neurotrophic factor (BDNF) expression is induced by melanocortins in astrocytes but BDNF actions in astrocytes are largely unknown. We hypothesize that BDNF may prevent astrocyte death resulting in neuroprotection. We found that BDNF increased astrocyte viability, preventing apoptosis induced by serum deprivation by decreasing active caspase 3 and p53 expression. The anti‐apoptotic action of BDNF was abolished by ANA‐12 (a specific TrkB antagonist) and by K252a (a general Trk antagonist). Astrocytes only express the BDNF receptor TrkB‐truncated isoform 1, TrkB‐T1. BDNF induced ERK, Akt, and Src (a non‐receptor tyrosine kinase) activation in astrocytes. Blocking ERK and Akt pathways abolished BDNF protection in serum deprivation‐induced cell death. Moreover, BDNF protected astrocytes from death by 3‐nitropropionic acid (3‐NP), an effect also blocked by ANA‐12, K252a, and inhibitors of ERK, calcium, and Src. BDNF reduced reactive oxygen species levels induced in astrocytes by 3‐NP and increased xCT expression and glutathione levels. Astrocyte‐conditioned medium (ACM) from untreated astrocytes partially protected PC12 neurons, whereas ACM from BDNF‐treated astrocytes completely protected PC12 neurons from 3‐NP‐induced apoptosis. Both ACM from control and BDNF‐treated astrocytes markedly reduced reactive oxygen species levels induced by 3‐NP in PC12 cells. Our results demonstrate that BDNF protects astrocytes from cell death through TrkB‐T1 signaling, exerts an antioxidant action, and induces release of neuroprotective factors from astrocytes.Open Science BadgesThis article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. image