A rapid, sustainable green, isocratic, and sensitive liquid chromatographic method was applied successfully for chlorpheniramine (CP) enantioseparation in the presence of common additive caffeine (CAF) in their synthetic mixtures and pharmaceutical preparations. The analytical separation was achieved in 17 min using a C8 column and a UV detector at 254 nm. An aqueous phosphoric acid (10 mM) containing dual-cyclodextrin 10 mM SβCD, and 10 mM βCD: ACN (75:25, v/v, pH 3.0) was utilized as a mobile phase. The proposed method was linear in the range of 15.5–250 μg/mL for CAF and 6.25–100.0 μg/mL for both d-chlorpheniramine (d-CP) and l-chlorpheniramine (l-CP). The proposed methods are rapid and exhibited good repeatability, accuracy, and sensitivity (RSD less than 2.0 %). The detection limits were 1.98 μg/mL (CAF), 0.58 μg/mL (d-CP), and 1.05 μg/mL (l-CP). The limits of quantitation were 5.99 μg/mL (CAF), 1.75 μg/mL (d-CP), and 3.17 μg/mL (l-CP). In accordance with the recommendations of the International Conference on Harmonization (ICH), the technique is validated. Sustainable chemistry, commonly referred to as green chemistry, aims to prevent or minimize the harmful effects that chemicals have on the environment. The AGREE and Complex GAPI metric techniques were used to test the suggested methodology's greenness, and the findings revealed a satisfactory level of greenness with a 0.62 score for AGREE and 11 green patches for Complex GAPI.