The pharmaceutical sector is seeking cost-effective analyzers that deliver precise, real-time data. This study aims to establish a correlation between the pharmaceutical industry and advancements in solid-contact ion-selective electrodes for quantifying chlorphenoxamine hydrochloride (CPX) concentration in various matrices. A comparative analysis of the performance between solid contact and liquid contact sensors showed that solid contact sensors outperformed their liquid contact counterparts in terms of durability, handling, and ease of integration. A sensor was developed using MWCNT and calix[8]arene as ionophore, resulting in a Nernstian potentiometric response for CPX across a linear range of 5.0×10−5 to 1.0×10−8 M. The slope of the response was 57.89 ± 0.77 mV/decade, and the standard potential was determined to be 371.9 ± 0.8 mV. The developed sensor exhibits notable intrinsic advantages, such as a rapid response time of 12 ± 2 seconds and an extended lifespan of 3 months. The sensor exhibiting optimal performance has been effectively employed for the analysis of CPX in different matrices, including pharmaceutical formulations, urine, and plasma. The developed method underwent validation in compliance with ICH requirements. Finally, the method’s greenness and whiteness were evaluated using five different tools and successfully compared to those obtained from the established reported method.