Analyzing varied concentrations of pharmaceutical active drug substances in dosage forms without any interferences using eco-friendly principles is more challenging. Hence, the aim of the present study is used to estimate Crotamiton (CTM) and Hydrocortisone (HCS) simultaneously by applying green analytical principles together with Analytical Quality by Design (AQbD)- rotatable central composite based approach using RP-UPLC based method development and validation. The study was intended to enhance efficiency and reduce environmental consequences, by reducing the toxic solvents/chemicals usage and waste emission. The separation was carried out through the aid of a Waters X-Bridge (C18 50 × 2.5 mm i.d, 1.7 µm) column with an optimized mobile phase for the determination of two drugs were ethanol:0.01 M ammonium acetatebuffer (pH 3.0) 30:70v/v at a flow rate of 0.3 ml/min. The measurement was made at aconcentration of 70–130 µg/ml for CTMand 1.75–3.75 µg/ml for HCS(R2 = 0.9998–0.9995). The results of the degradation study revealed that the drugs degraded under stressed conditions and the degradation products were identified using MS, and the proposed structures were depicted. The suggested methodology’s linearity, accuracy, and precision have been verified using ICHcriteria and green assessment tools, with environmentally acceptable results. This novel eco-friendly AQbD-based analytical approach could be readily adaptable by chemical and pharmaceutical industries for regular analysis without any regulatory barriers.