Purpose This study was performed to investigate the effect of omega-3 on the treatment of mood and sleep disorder induced by menopausal complications due to hormone therapy in patients with breast cancer. Methods A placebo, double-blind and controlled trial was designed in oncology-hematology outpatient’s clinic of Omid Hospital, Isfahan, Iran. First, sixty patients were screened by hospital anxiety and depression scale (HADS) for any baseline mood disorders and then divided into either intervention group who had received 2 grams’ omega-3 daily for 4 weeks or identical placebo. Then, the patients were considered to assess by center for epidemiological studies-depression scale (CES-D), profile of mood states (POMS), and Pittsburgh sleep quality index (PSQI) questionnaires at the baseline and after 4-week follow-up. Results Findings showed that the mean scores of CES-D (P = 0.002), POMS (P = 0.03), and PSQI (P = 0.04) were significantly lower in the intervention group than the control group. In the intervention group, mean scores of CES-D (P <0.001), POMS (P <0.001), and PSQI (P = 0.003) were significantly lower in post-intervention than pre-intervention. Mean changes in scores of CES-D (P = 0.01), POMS (P = 0.001), and PSQI (P = 0.02) were significantly higher in the intervention group than the control group. Conclusion Our findings revealed that omega-3 supplementation have the potential to reduce mood disorders as well as to improve sleep quality in terms of subjective sleep quality, delay in falling asleep, sleep delay, and sleep disturbance in patients with breast cancer.