Major depressive disorder (MDD) is a widespread mental health condition affecting over 280 million people worldwide and is a major contributor to the global burden of disease. Despite selective serotonin reuptake inhibitors (SSRIs) being the first line of treatment for MDD, 30-40% of patients do not achieve remission, with chronic low-level inflammation linked to treatment resistance. This study aimed to evaluate the efficacy of the anti-inflammatory drug ibuprofen compared to the SSRI fluoxetine in a mouse model of inflamed depression. The objective was to explore whether anti-inflammatory drugs could be effective treatments for MDD in patients resistant to conventional antidepressants due to chronic low-grade inflammation. Male C57BL/6 mice underwent chronic unpredictable mild stress and Bacillus Calmette-Guerin inoculation to induce depressive-like behavior and chronic low-grade inflammation, respectively. Following exposure to an enriched environment, mice were treated with fluoxetine, ibuprofen, or vehicle. Assessments included spontaneous activity, emotional and cognitive domains, and peripheral cytokine levels. Our results showed that both ibuprofen- and fluoxetine-treated groups exhibited a more rapid decrease of the liking-type anhedonia and reduced cognitive impairments during the place learning test compared to the vehicle group. Such effects were not associated with alterations in the peripheral immune response, as cytokine levels did not significantly differ between the treatment groups. These findings demonstrated that fluoxetine and ibuprofen improved the depressive-like phenotype in a mouse model of inflamed depression, suggesting that anti-inflammatory drugs could serve as potential alternative treatments, enhancing positive outcomes for individuals experiencing depression associated with inflammation and resistance to conventional antidepressants.