Currently, no pharmacotherapy is routinely used for obstructive sleep apnea (OSA). Recently, combined noradrenergic plus antimuscarinic agents have been evaluated for the treatment of OSA in several trials. This systematic review and meta-analysis following PRISMA guidelines investigated the efficacy and safety of this combination drug regimen for the treatment of OSA. Seven databases were systematically screened for randomized controlled trials (RCTs) studying combined noradrenergic plus antimuscarinic agents for OSA to April 2022. Nine RCTs were identified for systematic review and five for meta-analysis. There were significant differences between OSA patients taking noradrenergic plus antimuscarinic agents and placebo with respect to sleep apnea-hypopnea index [mean difference (MD) −11.27 events/h, 95%CI (−21.69, −0.84) events/h; P = 0.03]; nadir oxygen saturation [MD 5.06%, 95% CI (2.57, 7.55)%; P < 0.0001], and arousal index [MD -8.17 events/h, 95% CI (−15.01, −1.33) events/h; P = 0.02] but not sleep efficiency. Our systematic review revealed that drug therapy modestly improved loop gain and upper airway collapsibility but decreased arousal threshold. A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on one night significantly reduced OSA severity and improved OSA upper airway function. The long-term efficacy and safety of drug combinations in OSA patients now require further study.