As glutamatergic system dysfunction is involved in bipolar depression pathophysiology, the glutamate receptor modulators such as Ketamine have been applied as complementary medication for mood stabilizers. While the treatment is currently just the intravenous injection of a single dose, and there is no robust conclusion on Ketamine effectiveness or its side effects in bipolar patients, this study aimed to consider single- and double-dose intravenous injections of Ketamine in bipolar patients compared to the placebo. In a randomized, double-blind controlled clinical trial, 30 patients diagnosed with bipolar I and II disorders according to DSM-IV-TR (SCID-I) were randomly divided into three groups: the first group received an intravenous injection of Ketamine (0.5 mg/kg) and placebo with a three-day interval, the second group received two doses of Ketamine (0.5 mg/kg) in the same interval, and the third group received two placebo injections. Patients were assessed for depression, anxiety, and mania at various time points, including before the injection, 60 minutes after the injection, on the first, third, fifth, seventh, and 14th day, as well as at the end of the first month using the Hamilton Depression Rating Scale, Beck Anxiety Inventory, and Young Mania Scale, respectively. Data were analyzed using ANOVA and Repeated measure tests. The mean age of patients was 36.8 ± 7.9 years, with 18 females (60%) and 12 (40%) males. Depression and anxiety showed significant differences in both the single- and double-dose Ketamine groups over time (P < 0.01). Moreover, mania displayed significant changes during the study time in the single- and double-dose Ketamine groups, as well as the in the control group. However, during the study time, there were no significant differences observed in depression, anxiety, and mania among the three groups (P = 0.198, P = 0.416, and P = 0.540, respectively). Patients did not indicate any side effects during the study. Intravenous Ketamine administration may relieve depressive manifestations in bipolar patients. The findings suggest that a double dose of Ketamine does not lead to greater improvement than a single dose.