Neuroinflammation appears to be associated with the neurobiology of depression, and treatments targeting inflammation have shown promising results in depression. This meta-analysis examined the efficacy and safety of minocycline, an anti-inflammatory drug, for the treatment of depressive symptoms. A systematic electronic literature search was independently conducted by two investigators. Standardized mean differences (SMDs) and risk ratio (RR) with their 95% confidence interval (CI) were calculated using a random-effect model. Four RCTs (n = 211) were identified for meta-analysis. Minocycline showed a significant trend of improvement in depressive symptoms compared to placebo [4 RCTs, n = 190, SMD: -0.54 (95%CI:-1.12, 0.04), P = 0.07; I = 73%]. Subgroup analyses showed that minocycline was superior to placebo in improving depressive symptoms in studies of unipolar depression (3 RCTs, n = 151, SMD: -0.77 (95%CI:-1.32, −0.22), P = 0.006; I = 60%) and in studies using minocycline monotherapy [SMD: -1.06 (95%CI:-1.68, −0.44), P = 0.0008]. The rates of discontinuation due to any reasons [RR: 1.48 (95%CI: 0.79, 2.77), P = 0.22, I = 0%] and adverse drug reactions [RR: 0.32 to 1.98 (95%CI: 0.03, 14.74), P = 0.19 to 0.84, I = 0% to 31%] were similar between minocycline and placebo. Minocycline appears to be effective and well-tolerated in ameliorating depressive symptoms in unipolar depression. Future large RCTs with sufficient duration is needed to confirm the positive effects of minocycline in treating depressive symptoms.