The effects of celecoxib on a broad spectrum of mood disorders and on inflammatory parameters have not yet been comprehensively evaluated. The aim of this study was to systematically summarize the available knowledge on this topic. Data from both preclinical and clinical studies were analyzed, considering the efficacy and safety of celecoxib in the treatment of mood disorders, as well as the correlation of inflammatory parameters with the effect of celecoxib treatment. Forty-four studies were included. We found evidence supporting the antidepressant efficacy of celecoxib in a dose of 400 mg/day used for 6 weeks as an add-on treatment in major depression (SMD = −1.12 [95%Cl: −1.71,−0.52],p= 0.0002) and mania (SMD = −0.82 [95% CI:−1.62,−0.01],p= 0.05). The antidepressant efficacy of celecoxib in the above dosage used as sole treatment was also confirmed in depressed patients with somatic comorbidity (SMD = −1.35 [95% CI:−1.95,−0.75],p< 0.0001). We found no conclusive evidence for the effectiveness of celecoxib in bipolar depression. Celecoxib at a dose of 400 mg/d used for up to 12 weeks appeared to be a safe treatment in patients with mood disorders. Although an association between celecoxib response and inflammatory parameters has been found in preclinical studies, this has not been confirmed in clinical trials. Further studies are needed to evaluate the efficacy of celecoxib in bipolar depression, as well as long-term studies evaluating the safety and efficacy of celecoxib in recurrent mood disorders, studies involving treatment-resistant populations, and assessing the association of celecoxib treatment with inflammatory markers.