Nanosized adsorbents when used in potentiometric methods of analysis usually show better performance rather than the traditional potentiometric approach; this is attributed to the high specific surface area of the nanomaterial used in addition to the lack of internal diffusion resistance, thus improving their adsorption capacity. In the presented work, a rapid and sensitive potentiometric determination of chlorpheniramine maleate (CPM) and pseudoephedrine hydrochloride (PSE) in pure form, in pharmaceutical preparation, and in biological fluid was developed based on functionalized magnetic nanoparticles (Fe3O4). This strategy was compared with the classical potentiometric strategy. Three types of sensors were constructed using phosphotungstic acid (PTA), β-cyclodextrin (β-CD), and β-cyclodextrin-conjugated Fe3O4 magnetic nanoparticles for the potentiometric determination of each of CPM and PSE. The prepared sensors were characterized in regards to their composition, life duration, working pH range, and response time. The sensors have demonstrated promising selectivity to CPM and PSE in the presence of pharmaceutical formulation excipients, plasma matrix, and a diversity of both organic and inorganic interfering materials. The developed sensors have displayed good responses. Statistical comparison of the achieved results with a reported method has revealed no significant difference regarding both accuracy and precision.