Background: Psoriasis is a chronic autoimmune disease with limited treatment options in India. Methotrexate is a conventional therapy, while Secukinumab, a human monoclonal antibody against IL-17, is a newer option. Objective: To compare the safety and efficacy of Secukinumab versus Methotrexate in Indian patients with moderate to severe plaque psoriasis. Methods: This open-labeled, randomized, case-controlled study included 14 patients (7 per group) with moderate to severe plaque psoriasis. Group A received Secukinumab, while Group B received Methotrexate. Efficacy was assessed by PASI score reduction at Day 90, and safety was evaluated by laboratory investigations and adverse event reporting. Results: Secukinumab showed improvement in PASI score reduction (PASI 75) compared to Methotrexate (p=0.281). Secukinumab was also found to be safer, with fewer adverse events and no significant changes in laboratory parameters. Conclusion: Secukinumab is a more effective and safer treatment option for moderate to severe plaque psoriasis in Indian patients compared to Methotrexate. Further studies are needed to confirm these findings and establish Secukinumab as a viable treatment option in India.