ABSTRACT Objectives To substantiate the clinical efficacy and investigate the real-world effectiveness of the herbal medicinal product BNO 1016 in acute rhinosinusitis (ARS) in the context of antibiotic stewardship. Methods We performed a meta-analysis of the clinical trials ARhiSi-1 (EudraCT No. 2008-002794-13) and ARhiSi-2 (EudraCT No. 2009-016682-28) comprising 676 patients, analyzing the reduction of the Major Symptom Score (MSS) and improvement of the Sino-Nasal Outcome Test 20 (SNOT-20) by the herbal medicinal product BNO 1016. In addition, we performed a retrospective cohort study including 203,382 patients, comparing the real-life effectiveness of BNO 1016 in reducing ARS-related adverse outcomes in comparison to antibiotics and several other established therapies. Results Treatment with BNO 1016 ameliorated symptoms of ARS by reducing MSS by 1.9 points (p < 0.0001) and improved quality of life (QoL) for patients by improving SNOT-20 by 3.5 points (p = 0.001) in comparison to placebo. In patients with moderate/severe symptoms, the positive effects of BNO 1016 were even more pronounced (MSS: −2.3 points (p < 0.0001); SNOT-20: −4.9 points (p = 0.0158)). In addition, treatment with BNO 1016 was as effective or significantly more effective in reducing the risk for adverse ARS-related outcomes such as follow-up antibiotic prescriptions, sick leave ≥7 days or medical appointments due to ARS, especially when compared to antibiotics. Conclusion BNO 1016 is a safe and effective treatment for ARS that can help reduce the overuse of antibiotics.