Inflammatory diseases lead to excessive proinflammatory cytokine production (cytokine storms). The cytokine storms are highly lethal, so establishing an effective treatment is desirable. Recently, some of selective serotonin reuptake inhibitors (SSRIs), which are used to treat depression, have been reported to be effective in treating various inflammatory diseases, such as COVID-19. In this study, in order to elucidate which SSRI would be the most suitable as an anti-inflammatory drug, we investigated that the effect of 5 SSRIs on the production of inflammatory cytokine (Interleukin-6; IL-6) induced by macrophage activation induced in a Toll-like receptor (TLR)-dependent manner, and by T cell activation induced in a TLR-independent manner. In J774.1 murine macrophage cells, pretreatment with the SSRIs significantly suppressed IL-6 release induced by TLR3, TLR4, and TLR9 agonist. On the other hand, these SSRIs are also significantly suppressed IL-6 release induced by T cell activator in murine splenic lymphocytes. Our results show that fluoxetine has potent inhibitory effect on IL-6 production induced by various stimuli and low cytotoxicity among the 5 SSRIs. An examination of the structural requirements indicated that the N-methyl group of fluoxetine has a critical role in the inhibition of IL-6 production. Overall, our findings suggest that fluoxetine might be one of the preferred SSRI for further evaluation as an anti-inflammatory drug to treat cytokine storms.