Transdermal Drug Delivery System (TDDS) is an innovative approach delivering drugs through the skin at a controlled rate to enhance therapeutic efficacy and patient compliance. This study formulated Esomeprazole transdermal patches using HPMC with PVP and HPMC with Eudragit L100 polymers in varying ratios. Drug-excipient compatibility was confirmed via FT-IR. Formulated patches were evaluated for thickness, folding endurance, moisture content, weight uniformity, swelling index, water vapor transmission, and surface pH. In vitro studies demonstrated maximum systemic availability (93.14% and 92.12%), indicating high bioavailability. The study supports TDDS as an effective alternative dosage form for Esomeprazole. © 2020 Elsevier B.V., All rights reserved.