Simple, sensitive, and green ultraviolet spectrophotometric with chemometric support and chromatographic methods were designed and verified for the concurrent estimation of pantoprazole (PTZ) and vincamine (VIN). This co-administered mixture was determined for the first time in their pharmaceutical dosage forms with a high percentage of recoveries. Classical least squares (CLS), principle component regression (PCR), and partial least squares (PLS), are the three chemometric techniques applied in UV spectrophotometric analysis. An experimental design with two variables and five levels was utilized for models’ optimization. The optimized techniques were successfully verified and utilized to resolve their extensive zero-order spectral overlap within the wavelength span of 240–310 nm. In the chromatographic technique, the compounds were well separated on BDS HYPERSIL C8 column employing a mobile phase composed of phosphate buffer, 0.2% tri-ethylamine and acetonitrile (55:45% v/v), adjusting pH at 4.25. The flow speed was 1 mL/min using an isocratic mode for elution and UV detection at 230 nm. The studied drugs were separated in less than 5 min. The HPLC Method validation was carried out in accordance with the International Conference on Harmonization (ICH) guidelines. A comparative statistical analysis revealed no significant differences between the outcomes of the developed approaches and the reported spectrophotometric methods. A comprehensive sustainability profiling of the proposed methods was established and compared using the latest Blue Applicability Grade Index (BAGI), along with the most widely applicable metrics for greenness: the Analytical Eco-Scale (AES), GAPI and AGREE metrics, and the recent whiteness evaluation tool (RGB 12).