Introduction: Vernal keratoconjunctivitis (VKC) is a chronic bilateral allergic eye disease affecting children, causing significant morbidity. Despite its prevalence, there is no permanent cure, and severe cases pose management challenges. This study aimed to compare the efficacy of Rebamipide, Cyclosporine, and Olopatadine in treating severe VKC, assessing complications and relapse rates. Methods: A 16-month prospective study enrolled 270 VKC patients aged 4-20 years. Patients were randomized into three groups receiving Rebamipide, Cyclosporine, or Olopatadine. Standardized assessments were conducted at weeks 0, 2, 6, and 12, including clinical examinations and Bleik scoring. Statistical analysis employed ANOVA, Tukey’s post-hoc tests, and paired t-tests. Results: Significant age differences were observed among groups, with males predominantly affected. All treatments demonstrated efficacy, with Rebamipide showing consistent improvement in total subjective symptom scores (TSSS) and total objective ocular sign scores (TOSS) over 12 weeks. Complication rates were low. Conclusion: Rebamipide, Cyclosporine, and Olopatadine exhibited similar efficacy and safety profiles in treating severe VKC. Treatment, along with artificial tear and soft steroid, significantly reduced clinical symptoms and signs without serious adverse effects. Further multicentric studies are warranted for conclusive determination of drug regimen superiority. This research contributes valuable insights into managing VKC, especially in regions like northern India grappling with its increasing burden.