Background: Standard multi-drug therapy (MDT) with duration of 6-12 months is generally effective for treating leprosy. However, in cases of lepromatous (LL) and borderline lepromatous (BL) patients with high bacterial loads and complicated circumstances often faces non-adherence. Ofloxacin, a fluoroquinolone, has shown promising efficacy against Mycobacterium leprae in in-vitro and in-vivo studies, therefore accelerates bacterial clearance. Methods: This single-center retrospective cohort study investigated the effects of adding ofloxacin to MDT in 21 patients diagnosed with LL or BL leprosy at Cipto Mangunkusumo National Referral Hospital, Jakarta, Indonesia. Bacterial load and viability were tracked using the Bacteriological Index (BI) and Morphological Index (MI), and were compared before and after the patients were given ofloxacin. Findings: Adding ofloxacin to MDT led to a significant reductions in both BI and MI. The median MI dropped to zero after six months of combined treatment (p<0.001), with significant differences between baseline and 6, 9, and 12-months. BI also significantly declined (p=0.007), with significant reductions between baseline and 3, 6, 9, and 12-month assessments. The proportion of patients reaching an MI of zero also steadily increased. Interpretation: Ofloxacin as an adjunctive therapy to MDT substantially improves treatment of leprosy with high bacterial and morphological index. Faster bacterial clearance prevent prolonged treatment duration, potentially improving adherence, outcomes and reducing relapse risk. Ofloxacin is the only second-line leprosy treatment covered by the national health insurance in Indonesia. Earlier initiation of this adjunctive therapy may offer greater benefits. Copyright: © 2025 Priyanto MH et al.