Abstract Airway clearance is a cornerstone of management in non–cystic fibrosis bronchiectasis (NCFB), a chronic condition characterized by airway inflammation, mucus hypersecretion, and impaired mucociliary clearance, leading to recurrent infections and progressive lung function decline. Despite strong guideline recommendations for airway clearance techniques (ACTs), the quality of evidence supporting the use of any particular devices remains low. Simeox is a novel oscillatory ACT device designed to promote mucus fragmentation and facilitate expectoration. This study aimed to evaluate the effectiveness and safety of home-based Simeox therapy compared with standard physiotherapy in patients with NCFB and chronic mucus hypersecretion. This two-center, prospective randomized controlled pilot study enrolled adults with HRCT-confirmed NCFB, daily mucus production exceeding 10 mL, and a pulmonary exacerbation at baseline. Participants were randomized to receive either Simeox therapy in addition to standard care or standard care alone, including conventional ACTs. All patients received in-hospital training and continued their assigned therapy at home for six weeks, with a total follow-up duration of two months. The primary outcome was change in respiratory symptoms assessed using the Chronic Airways Assessment Test (CAAT). Secondary outcomes included lung function (FEV₁, FVC), exercise capacity measured by the six-minute walk test (6MWT), dyspnea assessed using the Medical Research Council (MRC) scale, and exacerbation rates. Statistical analyses included unadjusted comparisons and confirmation using generalized estimating equations (GEE) to account for baseline imbalances. Fifty patients were enrolled (median age 67.5 years [IQR 52.25–71]; 76% female), with no withdrawals or deaths during follow-up. Baseline disease severity, radiological extent of bronchiectasis, and microbiological characteristics were largely comparable between groups, although prior hospitalizations and chronic sinusitis were more frequent in the Simeox group. Simeox therapy resulted in a significantly greater improvement in CAAT scores compared with standard care, indicating a clinically meaningful reduction in respiratory symptom burden. No significant between-group differences were observed in spirometric parameters or 6MWT distance. Exacerbation rates were similar between groups, and no severe adverse events were reported. The study findings suggest that Simeox therapy may be associated with greater improvement in respiratory symptoms among patients with NCFB and chronic mucus hypersecretion. However, larger, adequately powered randomized controlled trials are needed to confirm its long-term benefits and to identify the patient subgroups most likely to benefit from this therapy.