The ion-sensitive field-effect transistor is a well-established electronic device typically used for pH sensing. The usability of the device for detecting other biomarkers in easily accessible biologic fluids, with dynamic range and resolution compliant with high-impact medical applications, is still an open research topic. Here, we report on an ion-sensitive field-effect transistor that is able to detect the presence of chloride ions in sweat with a limit-of-detection of 0.004 mol/m3. The device is intended for supporting the diagnosis of cystic fibrosis, and it has been designed considering two adjacent domains, namely the semiconductor and the electrolyte containing the ions of interest, by using the finite element method, which models the experimental reality with great accuracy. According to the literature explaining the chemical reactions that take place between the gate oxide and the electrolytic solution, we have concluded that anions directly interact with the hydroxyl surface groups and replace protons previously adsorbed from the surface. The achieved results confirm that such a device can be used to replace the traditional sweat test in the diagnosis and management of cystic fibrosis. In fact, the reported technology is easy-to-use, cost-effective, and non-invasive, leading to earlier and more accurate diagnoses.