This work highlighted the counterion association of diphenhydramine hydrochloride (DPC) and chlorpheniramine maleate (CPM) with anionic sodium tetradecyl sulfate (STS) by conductivity, fluorescence, and UV spectrophotometer measurements. The presence of drugs and the formation of premicellar aggregates of STS were highlighted. The modified Corrin–Harkins CH approaches assessed the STS counterion binding values B = 0.300 for DPC and 0.379 for CPM in the aqueous media at 25 °C. The counterion binding constant (βc) and Gibb’s free energy of micellization (ΔGmic°) were increased and became more negative, suggesting that the drug–surfactant interaction was controlled by electrostatic interaction. Furthermore, the spectral study evaluated that the three isosbestic points for CPM and one isosbestic point for DPC in the STS micelles were observed, which confirmed that CPM was more binding than DPC with the STS micelles. The differential absorbance spectra study was applied to UV spectra to determine the binding constants (Kb) of 2.232 and 2.837 and partition coefficients (Kx) of 286.64 and 3209.21 for DPC and CPM in the presence of STS micelles. The findings demonstrated that the CPM molecules have been associated with the Palisade layer of the STS micelles, and the DPC molecules were bound to the Stern layer of the STS micelles. Finally, we came to the conclusion that ionic drugs could improve the micellization capabilities of surfactants, which might be useful for choosing the best excipients for pharmaceutical applications