BackgroundIntegrating green chemistry principles into analytical processes is vital for sustainability and accuracy. AimThis study is dedicated to finding eco-friendly solutions that replace harmful substances and reduce waste production. The suggested work examined eight tools for assessing the greenness and sustainability of a newly validated RP-HPLC technique that quantitatively determines levodopa (LEV) and carbidopa (CAR) drugs in their bulk and pharmaceutical formulations. We also incorporated the lean six sigma methodology to ensure accuracy and efficiency. MethodThe optimal liquid chromatographic conditions (HPLC) for achieving the highest resolution and results in our method are as follows: employing a mobile phase composition consisting of a mixture of phosphate buffer pH 2.2 and ethanol (90:10 v/v) at a flow rate of 1 mL/min, using a C18 column (150 mm × 4.6 mm) and employing an isocratic mode of elution at a wavelength of 280 nm. ResultsThe calibration curves were established for LEV and CAR in the 3–50 μg/mL range to study the linearity with coefficients of determination (R2 ∼0.999). The study determined that the limits of detection (LOD) and quantification (LOQ) for LEV were 1.95 μg/mL and 5.93 μg/mL, respectively. Meanwhile, the results for CAR were 0.67 μg/mL and 2.04 μg/mL for LOD and LOQ, respectively. The developed method has demonstrated accuracy and validity in the simultaneous determination and quantification of LEV and CAR, with a relative standard deviation (RSD) of less than 2%. The method's accuracy was confirmed through recovery studies, demonstrating significant results within the acceptable range of 98–102%. Specifically, the recovery test values for LEV and CAR were 99.75% and 98.97%, respectively. ConclusionThe specificity and selectivity of the developed method have been revealed through forced degradation studies conducted through The International Council for Harmonization (ICH) criteria. The technique could determine and quantify the two drugs even in the presence of their degradants. Our proposed approach beats the previous HPLC methods in adherence to green chemistry principles, providing reliable and precise outcomes with better qualitative and quantitative metrics. It's the most effective and eco-friendly solution for chemical analysis.