<p>To estimate aspirin (ASP) and vonoprazan fumarate (VONO) in synthetic mixture simultaneously, a new stability-indicating thin-layer chromatographic (TLC) approach was developed and validated. A three-level factorial design was employed to statistically optimize key chromatographic parameters, including mobile phase composition, chamber saturation time, and solvent front. Ethyl acetate–methanol–2% acetic acid (7:2:1, <i>V/V</i>) was used as the mobile phase to produce chromatographic separation on precoated silica gel 60 F₂₅₄ TLC plates, with densitometric detection at 268 nm. The method demonstrated excellent linearity, accuracy, and precision along with good specificity, robustness, and sensitivity (limit of detection and limit of quantification), confirming its reliability. Studies of forced deterioration in acidic, basic, oxidative, thermal, and photolytic environments verified the method’s capacity to indicate stability. The method was validated as per the International Council for Harmonisation guidelines and successfully applied for the simultaneous estimation of ASP and VONO in marketed formulation.</p>