A validated simple, novel, and rapid spectrofluorimetric method was developed for the determination of some non-sedating antihistamines (NSAs); namely cetirizine (CTZ), ebastine (EBS), fexofenadine (FXD), and loratadine (LOR). The method is based on measuring the native fluorescence of the cited drugs after protonation in acidic media and studying their quantitative fluorescence intensity – structure relationships. There was a linear relationship between the relative fluorescence intensity and the concentration of the investigated drug. Under the optimal conditions, the linear ranges of calibration curves for the determination of the studied NSAs were 0.10–2.0, 0.20–6.0, and 0.02–1.0 μg/mL for (CTZ, FXD), (EBS), and (LOR); respectively. The factors affecting the protonation of the studied drugs were carefully studied and optimized. The method was validated according to ICH guidelines. The suggested method is applicable for the determination of the four investigated drugs in bulk and pharmaceutical dosage forms with excellent recoveries (97.67–103.80 %). Quantitative relationships were found between the relative fluorescence intensities of the protonated drugs and their physicochemical parameters namely: the pKa, log P, connectivity indexes (χv)andtheirsquares. Regression equations (76) were obtained and not previously reported. Six of these equations were highly significant and used for the prediction of RFI of the studied NSAs.