Antihistamines are widely used to alleviate the symptoms caused by allergic reactions. Most of these drugs have zwitteriónicas and/or amphoteric characteristics, which confer additional analytical challenges. This work aimed to develop a single eco-friendly and efficient chromatographic methods for analysis of seven antihistamines, namely, azelastine HCl, desloratadine, ebastine, fexofenadine HCl, ketotifen, loratadine, and olopatadine HCl. The separations were obtained using RP C-18 LUNA (150x4.6mm, 5 μm) column. The mobile phase consisted of acetonitrile and acidified water (pH 2.1) in the following proportion: 15:85, v/v for desloratadine, 25:75, v/v for ketotifen and olopatadine, 32:68, v/v for fexofenadine, 35:65, v/v for azelastine and loratadine, and 45:55, v/v for ebastine. All separations were obtained in less than 7.0 min. A prototype method was fully validated and applied in the assay of azelastine HCl in nasal solutions. The proposed methods for analysis of seven antihistamines are highly efficient, selective, and sensitive. Moreover, all methods can be considered excellent in terms of greenness, with total organic residue < 2.5 mL/analysis. An improved gradient method is also described for separation of azelastine HCl and its related impurities.