Background <p>Leprosy reaction is inflammation caused by the body’s immune system attacking the leprosy bacteria. If left untreated or improperly managed, it may lead to irreversible nerve damage, causing mortality, disability, and physical deformities. Oral prednisolone is a recommended drug to manage these reactions. Despite this, the treatment outcome and safety of prednisolone in treating leprosy reactions in clinical practices have not studied well. Thus, this study aimed to assess the status and factors of treatment outcomes and safety of prednisolone in the treatment of leprosy reactions.</p> Methods <p>A hospital-based retrospective cohort study was conducted. Data were collected using a data abstract form, entered into Epi-Data version 4.0, and then exported to SPSS version 25 for further analysis. Descriptive statistics were computed to get summary results, and binary and multinomial logistic regression analyses were used to predict factors that affect the treatment outcome and safety of prednisolone.</p> Results <p>In this study, 262 patients’ record files were reviewed. The median age of patients was 30 (IQR 25–42.5) years. Two-thirds (66.8%) of patients were males. Of 262, only 62.2% of the patients improved from the leprosy reactions with prednisolone treatment. Patients with WHO disability grade-0 showed more improvement than those with higher grades. Furthermore, out of 262 patients, 79.4% experienced at least one adverse event during the course of treatment. The starting dose of prednisolone and treatment duration were significantly associated with the occurrence of the adverse events.</p> Conclusion <p>A considerable proportion of the patients didn’t show improvement in their reaction status with prednisolone for both type one and two reactions. The prevalence of adverse events was higher, and the magnitude was proportional to duration and dose of prednisolone, suggesting the need to optimize treatment strategies.</p> Clinical Trial <p>Not applicable.</p>