Paroxetine, a representative of serotonin reuptake inhibitors, has recently gained attention due to its anti‐inflammatory properties. However, underlying mechanisms responsible for its immunosuppressive effects remain to be unveiled. To understand the responsible signaling mechanisms, we examined paroxetine's effect on the Janus kinase 2‐signal transducer and activator of transcription 3 (JAK2‐STAT3) signaling pathway on lipopolysaccharide + phytohemagglutinin‐induced human peripheral blood mononuclear cells culture. We also evaluate the possible dependency of paroxetine immunomodulation effects on the 5‐HT system of immune cells. Our results indicated that paroxetine attenuates proinflammatory cytokine production (interleukin‐1β [IL‐1β], IL‐17, and tumor necrosis factor‐α) and increases expression of IL‐10 and JAK2/STAT3 evidence for macrophages polarization to M2 subset and functional dendritic cells depletion. In conclusion, paroxetine can exert its anti‐inflammatory effects via both the 5‐HT systems present in immune cells and the JAK2‐STAT3 pathway. Our results also suggest that paroxetine exerted its immunosuppressive effects partially via serotonin. Nonetheless, JAK2/STAT3‐modulated paroxetine effects were independent of serotonin, hence sufficiently applicable for inflammation repression.