With the advantages of small size, reliability, rapid response, compatibility to standard CMOS technology and on-chip signal processing, Ion-Sensitive Field Effect Transistor (ISFET)-based transducers are increasingly being applied in physiological data acquisition and environment monitoring. This paper presents a signal processing Application Specific Integrated Circuit (ASIC) and a discrete temperature compensation chip design of a potentiometric ISFET-based chemical sensor. To assure the measurement of a correct pH value, the two-point calibration circuitry based on the response of standard pH 4 and 7 buffer solution has been implemented by using Algorithmic State Machine hardware algorithms. For battery power consideration, the proposed signal processing ASIC consisting of low voltage (3 V) mixed signal modules has been developed and fabricated in a 0.5 μm CMOS technology. The results demonstrate small differences of pH response of ISFET's operating with and without ASIC device, i.e. only the order of 0.1 mV/pH with respect to sensitivity. Furthermore, using the temperature compensating circuitry reduces the ISFET temperature coefficient to +0.15 mV/ o C, and hence results in a lower pH value variation of -0.0023pH/ o C. It was shown that more accurate pH measurement can be concluded with the proposed ASIC and V T extractor circuitry.