Cyclosporine A (CsA) is effective in treating moderate-to-severe atopic dermatitis (AD). This systematic review and meta-analysis aimed to summarize the effectiveness and safety of low-dose (<4 mg/kg) versus high-dose (≥4 mg/kg) CsA and other systemic immunomodulatory agents in patients with AD. Five randomized controlled trials met the inclusion criteria. The meta-analysis included 159 patients with moderate-to-severe AD who were randomized to receive low-dose CsA, and 165 patients randomized to receive high-dose CsA and other systemic immunomodulatory agents. We found that low-dose CsA was not inferior to high-dose CsA and other systemic immunomodulatory agents in reducing AD symptoms [standard mean difference (SMD) -1.62, 95% confidence interval (CI) -6.47; 3.23]. High-dose CsA and other systemic immunomodulatory agents showed a significantly lower incidence of adverse events [incidence rate ratio (IRR) 0.72, 95% CI 0.56; 0.93], however, after sensitivity analysis, there was no difference between the two groups except for one study (IRR 0.76, 95% CI 0.54; 1.07). Regarding serious adverse events requiring discontinuation of treatment, we observed no significant differences between low-dose CsA and other systemic immunomodulatory agents (IRR 1.83, 95% CI 0.62; 5.41). Our study may justify the use of low-dose CsA rather than high-dose CsA and other systemic immunomodulatory agents in moderate-to-severe AD.