Depression might manifest itself with a chronic inflammation in different tissues and organs independent of the central nervous system. Psoriasis, Crohn's disease, and fibromyalgia are among these disorders accompanying the depression. The treatment options for these conditions are a combination of the anti-depressants and anti-inflammatory agents. Bupropion has been widely utilized as an anti-depressant. It has been preferred among the patients with Crohn's disease and psoriasis due to its anti-inflammatory role, as well. In this study, we aimed to decipher its target in the immune system. Macrophages were activated in the presence of LPS and increasing concentrations of the bupropion. TNF-α, IL-6, GM-CSF, and IL-12p40 cytokines' production levels were measured by ELISA to compare it to the control groups. These cytokines have been associated with the aggressive inflammation in different tissues. Moreover, p38 and PI3K proteins' phosphorylated levels were measured to examine whether bupropion acts through these pathways or not. Our results suggest that bupropion had anti-inflammatory action on the activated macrophages and its mechanism of action was partially dependent on p38 but independent of PI3K pathways.