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Respiratory tract infections (RTIs) are the leading cause of antibiotic prescriptions, primarily due to the risk for secondary bacterial infections. In this study, we examined whether <i>Echinacea</i> could reduce the need for antibiotics by preventing RTIs and their complications, and subsequently investigated its safety profile. A comprehensive search of EMBASE, PubMed, Google Scholar, Cochrane DARE and clinicaltrials.gov identified 30 clinical trials (39 comparisons) studying <i>Echinacea</i> for the prevention or treatment of RTIs in 5652 subjects. <i>Echinacea</i> significantly reduced the monthly RTI occurrence, risk ratio (RR) 0.68 (95% CI 0.61–0.77) and number of patients with ≥1 RTI, RR = 0.75 [95% CI 0.69–0.81] corresponding to an odds ratio 0.53 [95% CI 0.42–0.67]. <i>Echinacea</i> reduced the risk of recurrent infections (RR = 0.60; 95% CI 0.46–0.80), RTI complications (RR = 0.44; 95% CI 0.36–0.54) and the need for antibiotic therapy (RR = 0.60; 95% CI 0.39–0.93), with total antibiotic therapy days reduced by 70% (IRR = 0.29; 95% CI 0.11–0.74). Alcoholic extracts from freshly harvested <i>Echinacea purpurea</i> were the strongest, with an 80% reduction of antibiotic treatment days, IRR 0.21 [95% CI 0.15–0.28]. An equal number of adverse events occurred with <i>Echinacea</i> and control treatment. <i>Echinacea</i> can safely prevent RTIs and associated complications, thereby decreasing the demand for antibiotics. Relevant differences exist between <i>Echinacea</i> preparations.