A novel paper-based ion-selective organic electrochemical transistor (IS-OECT) for the detection of potassium and creatinine is presented. First, ion-selective membranes are cast onto thick-film transistor channels to create highly sensitive and selective ion sensors. Since optimum performance is obtained at 0 V gate voltage, several sensors can be used in parallel with a single gate connected to a common grounded source electrode. Then, to further demonstrate the detection capabilities, the IS-OECTs were integrated with a purposely designed differential amplifier. This allows the conversion of current signals into a voltage output, facilitating comparison with potentiometric systems and the use of low-cost commercial data acquisition platforms. The evaluation of the performance in artificial serum is performed in clinically relevant ranges, which comprise 2.4-5.75 mM for potassium and 30-140 μM for creatinine. These results highlight the potential of the IS-OECT framework as a cost-effective, portable, and reliable solution for point-of-care diagnostics.