Objectives: To systematically examine the effectiveness, tolerability, and safety of brexanolone infusion in treating postpartum depression (PPD). Methods: Randomized controlled trials (RCTs) were included. Results: Two articles reporting 3 RCTs with 4 active arms (n = 267) covering 156 women with PPD receiving brexanolone infusion and 111 women with PPD on placebo were included. Compared with placebo, women suffering from PPD who received brexanolone had significantly greater response that started after 24 h (risk ratio (RR)=1.34, 95%CI 1.03–1.73), peaked at 36 h (RR = 1.50, 95%CI 1.06–2.13, P = 0.02) and lasted until Day 7 (RR = 1.32, 95%CI 1.01–1.73). Similarly, PPD women treated with brexanolone had significantly greater remission starting at 24 h (RR = 1.86, 95%CI 1.03–3.34), peaking at 60 h (RR = 2.20, 95%CI 1.31–3.70) and lasting until 72 h (RR = 1.96, 95%CI 1.41–2.72). Brexanolone infusion led to significantly higher rate of discontinuation for any reasons (RR = 2.68, 95%CI 1.35–5.32). Discontinuation due to intolerability and adverse drug reactions was similar between the active agent and placebo. Conclusion: A single brexanolone infusion appears to have ultra-rapid antidepressant effect for PPD, lasting for up to 1 week. The short and long-term therapeutic effect of brexanolone needs to be examined in large-scale RCTs.