Depression is very common in asthmatic patients and may increases risk for morbidity and mortality. The present work aimed to investigate the protective effect of fluoxetine, on behavioral and biochemical changes, associated with ovalbumin (OVA) - induced bronchial asthma and depression in rats. Rats were sensitized with intraperitoneal administration of OVA plus aluminum hydroxide for 3 consecutive days then at day 11 followed by OVA intranasal challenge at days 19, 20, 21. Rats were either pretreated with dexamethasone, fluoxetine10mg/kg or fluoxetine 20mg/kg. At the end of the experiment, various tests were performed, including open field, forced swimming and respiratory function tests. Blood was drawn for serum IgE detection. Finally, rats were euthanized, brain-derived neurotrophic factor (BDNF) was estimated in bronchoalveolar lavage (BAL) fluid and lung content of reduced glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α) and interleukin 4 (IL-4) were determined. Histopathological study was also performed. The results showed that fluoxetine significantly ameliorated OVA- induced biochemical and behavioral changes. Fluoxetine may protect against OVA-induced asthma and depression in rats. This effect may be mediated at least in part by its antioxidant, anti-inflammatory and immunosuppressant effect.