Background: Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory condition characterized by persistent airway infection and inflammation, often requiring long-term antibiotic therapy. Inhaled and oral antibiotics are two primary treatment modalities, each with distinct pharmacokinetic profiles and therapeutic outcomes. This study compares the pharmacokinetics and efficacy of inhaled versus oral antibiotics in managing NCFB to determine the optimal treatment approach. Materials and Methods: A randomized controlled trial was conducted on 100 patients diagnosed with NCFB. Patients were divided into two groups: Group A (n=50) received inhaled antibiotics (tobramycin 300 mg BID), while Group B (n=50) received oral antibiotics (levofloxacin 500 mg OD). Plasma and sputum antibiotic concentrations were measured at 1, 4, and 8 hours post-administration. Clinical efficacy was assessed based on sputum bacterial load, forced expiratory volume in 1 second (FEV₁), and exacerbation frequency over 12 weeks. Statistical analysis was performed using ANOVA and paired t-tests, with significance set at p< 0.05. Results: Inhaled antibiotics demonstrated significantly higher sputum concentrations (15.2 ± 3.1 µg/mL) compared to oral administration (4.5 ± 1.2 µg/mL, p< 0.01), while systemic absorption was lower in the inhaled group (2.1 ± 0.8 µg/mL vs. 6.8 ± 1.5 µg/mL, p< 0.01). Clinical response was superior in the inhaled group, with a 42% reduction in bacterial load compared to 28% in the oral group. FEV₁ improvement was also higher in Group A (8.5% vs. 5.2%, p< 0.05). The frequency of exacerbations was significantly lower in the inhaled group (0.9 episodes vs. 1.6 episodes per patient, p< 0.05). Conclusion: Inhaled antibiotics exhibit superior local drug delivery, leading to higher airway drug concentrations, enhanced bacterial eradication, and improved clinical outcomes compared to oral antibiotics in NCFB treatment. The reduced systemic absorption of inhaled antibiotics also minimizes adverse effects, suggesting they may be a preferable therapeutic option for managing NCFB.