<p>Hypertension is a chronic medical condition characterized by elevated arterial blood pressure. It is one of the five leading risk factors for disability-adjusted life years worldwide. This study reports the development and validation of a ZIC-HILIC method coupled with UV detection for the simultaneous determination of aliskiren and amlodipine in pharmaceutical formulations. Two lab-made ZIC-HILIC columns (ZIC-2 and ZIC-5) were employed to assess retention behavior under varying chromatographic conditions. The effects of acetonitrile proportion, acetate buffer concentration, and pH on analyte separation were systematically examined. Optimal resolution was achieved using a mobile phase comprising 80% acetonitrile and 20% acetate buffer (20 mM, pH 4.7) at a flow rate of 0.75 mL/min, with detection at 243 nm. The method exhibited excellent linearity over the concentration ranges of 0.1–14.50 μg/mL for aliskiren and 0.1–7.5 μg/mL for Amlodipine. The residual plots indicated that the errors are normally distributed and exhibit constant variance. Five well-established metrics for estimating the environmental friendliness of chemical methods were studied. Analytical Eco-Scale (AES), Analytical GREEnness metric (AGREE), National Environmental Method Index (NEMI), Blue Analytical Greenness Index (BAGI), and Green Analytical Procedure Index (GAPI) were found to be effective and reliable for greenness assessment.</p>