(1) Background: 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. (2) Methods: Clinical efficacy: We performed a meta-analysis of the clinical trials ARhiSi-1 and ARhiSi-2 comprising 676 patients, analysing the reduction of the Major Symptom Score (MSS) and improvement of SNOT-20. Real-world effectiveness: 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. (3) Results: Clinical efficacy: 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)) compared to placebo. Real-world effectiveness: 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. (4) Conclusions: BNO 1016 is a safe and effective treatment for ARS that can help reduce the overuse of antibiotics.