Chronic depression is a complex disorder with huge societal repercussions. Although currently used antidepressant drugs are generally effective, most of these drugs display serious adverse effects. Moreover, the incompletely elucidated pathological mechanisms of depression constitutes a bottleneck in development of antidepressants. Among them, the field targeting neuroinflammation, which is associated with depression, remains unexplored. Here, we evaluated neuroprotective and antidepressant properties of a phenolic phytochemical, hydroxytyrosol (HT). We observed that HT treatment alleviated depressive-like behaviors in rodent models of learned helplessness (LH), chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). HT improved hippocampal neuronal injury with modulation of microglia activation, inflammatory cytokines production, mitochondrial damage and BDNF signaling pathway, as well as the cellular level. In addition, targeted metabolomics results showed that HT compensated for the neurotransmitters deficiency and inhibited the tryptophan-kynurenine metabolism in the brain of CUMS rats. RNA-Seq studies confirmed that the antidepressant effect of HT was modulated by BDNF signaling pathways closely associated with the functions of nerve fibers, myelin formation, microglia differentiation, and nerve regeneration. There is potential for developing neuroprotective agents based on HT to treat depression disorders caused by inflammation-related neuronal injury.