Depression is one of the most common disorders appearing following a stroke, and is also a major factor limiting recovery and rehabilitation in stroke patients. Antidepressants are the most common prescribed treatment for depression and have shown to have anti-inflammatory properties within the central nervous system (CNS). The major source of pro-inflammatory factors within the CNS is from activated microglia, the innate immune cells of the CNS. Antidepressants have been shown to promote midbrain and hippocampal neuronal survival following an ischemic insult and this survival is mediated through the anti-inflammatory effects on microglia, but the effects on cortical neuronal survival after this insult have yet to be investigated. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and selective serotonin-reuptake inhibitors [SSRIs]) on the release of inflammatory factors and amino acids from activated microglia and whether altering this release could affect cortical neuronal viability after an ischemic insult. Primary microglia were treated with 1 μg/ml LPS and/or 10 μM antidepressants, and the various factors released into medium were assayed. Co-cultures consisting of microglia and primary cortical neurons were used to assess the effects of antidepressant-treated activated microglia on the viability of ischemic injured neurons. Of the antidepressants tested, most decreased the release of the proinflammatory factors nitric oxide, tumor necrosis factor-alpha, and interleukin 1-beta from activated microglia. Fluoxetine and citalopram, the SSRIs, decreased the release of the amino acids glutamate and d-serine from LPS-activated microglia. oxygen-glucose deprived (OGD) cortical neurons cocultured with LPS-activated microglia pre-treated with fluoxetine and citalopram showed greater survival compared to injured neurons co-cultured with untreated activated microglia. Microglial release of glutamate and d-serine was shown to be the most important factor mediating neuronal survival following antagonism studies. To our knowledge, our results demonstrate for the first time that fluoxetine and citalopram decrease the release of glutamate and d-serine from LPS-activated microglia and this causes an increase in the survival of OGD-injured cortical neurons after co-culture.