After receiving interferon (IFN) treatment, a lot of people with chronic illnesses and viral infections experience significant depression. NSAIDs can reduce the stress hormone release and IFN-induced activation of inflammatory cytokines. We investigated the effects of etoricoxib on the biochemical and behavioral changes induced by acute IFN-exposure in the brain. After being outbred for six days, adult Swiss Albino female mice developed depression in response to INF (16 105 IU/kg, body weight). Behavioral and biochemical reactions were seen after oral administration of etoricoxib (10 mg/kg) and amitriptyline (10 mg/kg). Similar to amitriptyline in antidepressant effects was the drug used in the trial. Etoricoxib administration significantly changed the number of squares traversed and rearing incidences in the open field test results when compared to the control and vehicle+IFN- groups. Etoricoxib (ET) reduced plasma nitrite (p0.001) in comparison to the vehicle-treated group, demonstrating a reduction in nitrosative stress. Etoricoxib (ET) and amitriptyline (AMI) both decreased plasma corticosterone (p 0.001). ET and amitriptyline both reduced brain MDA in contrast to the vehicle+IFN- group (p=0.05 and p=0.001, respectively). Not to mention, the medication significantly reduced brain catalase function. IFN-a-induced depression may be lessened by NSAIDs through regulating neurochemical changes