Due to the rise in the social and economic costs of depression, new antidepressant medication with fewer side effects should be found. Several studies have shown that an association exists between omega-3 polyunsaturated fatty acids (omega-3 PUFAs) and depression. However, this association has not been clear enough in the elderly with mild to moderate depression. Sixty-six inhabitants of Kahrizak Charity Foundation participated in this double-blind, randomized, placebo-controlled study. Each participant was a parts per thousand yen 65 years of age, had a Mini Mental State Exam of a parts per thousand yen 22, and had scores ranging from 5 to 11 on the Geriatric Depression Scale-15 (GDS-15). During the 6 months, the drug group was treated daily with one gram of fish oil capsule containing 300 mg of both eicosapentaenoic acid and docosahexaenoic acid. No significant differences were noted between the groups in regard to level of education, use of antidepressant drugs, alcohol, tobacco use, history of chronic diseases, age, body mass index (BMI), high-sensitive C-reactive protein (hs-CRP), total cholesterol, and GDS-15 scores at baseline. After adjusting for cholesterol, BMI, and history of thyroid dysfunctions, a statistically significant difference was seen in GDS-15 scores between both groups. Furthermore, treatment with omega-3 PUFAs was clinically more effective in treating depression in comparison with the placebo. In this study, low-dose omega-3 PUFAs had some efficacy in the treatment of mild to moderate depression in elderly participants.