Interleukin-33 (IL-33) is an inflammatory cytokine that promotes allergic disease by activating ILC2, Th2 cells, and mast cells. IL-33 is increased in asthmatics, and its blockade suppresses asthma-like inflammation in mouse models. Therefore, clinical interventions targeting IL-33 may be beneficial for allergic disease. We have sought ways of re-purposing FDA-approved drugs for use in allergic inflammation. Because drugs in the selective serotonin reuptake inhibitor class (SSRIs) have documented anti-inflammatory effects, we tested the hypothesis that SSRIs can attenuate mast cell function. We show that the SSRI fluoxetine inhibits IL-33-mediated cytokine production in mouse bone marrow derived mast cells in vitro and reduces IL-33-induced peritonitis in vivo. These data indicate that fluoxetine may be an effective therapeutic for IL-33- and mast cell-associated diseases.