Microglia are resident brain cells that regulate neuronal development and innate immunity. Microglia activation is involved in the cellular response to neuroinflammation, thus representing a possible target for pharmacological strategies aimed to counteract the onset and progression of brain disorders, including depression. In this sense, antidepressant drugs have been reported to reduce neuroinflammation by acting on glial cells, too. Herein, the potential anti-inflammatory and neuroprotective effects of trazodone (TRZ) on the microglial HMC3 cell line were investigated. HMC3 cells were activated by a double inflammatory stimulus (LPS and TNF-α, 24 h each), and the induction of inflammation was demonstrated by i) the increased expression levels of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) and Ionized calcium-Binding Adapter molecule 1 (IBA-1), and ii) the increased release of interleukin 6 (IL-6) and Transforming Growth Factor-beta (TGF-β). TRZ effects were evaluated by treating HMC3 cells for 24 h before (pre-treatment) and after (post-treatment) the double inflammatory stimulus. Notably, both TRZ treatment approaches restored microglia, significantly decreasing the expression of NF-kB and IBA-1, and the release of the cytokines IL-6 and TGF-β. Moreover, TRZ prevented and reduced the release of quinolinic acid (QUIN), a known neurotoxic kynurenine metabolite, demonstrating a potential neuroprotective effect. In this sense, neuronal-like cells were incubated with conditioned media collected from microglial cells previously treated with LPS-TNF-α in the absence or in the presence of TRZ to evaluate cell viability. Overall, for the first time, this study suggests anti-inflammatory and neuroprotective effects of TRZ on human microglia.