This paper presents a robust, low-power and compact ion-sensitive field-effect transistor (ISFET) sensing front-end for pH reaction monitoring using unmodified CMOS. Robustness is achieved by overcoming problems of DC offset due to trapped charge and transcoductance reduction due to capacitive division, which commonly exist with implementation of ISFETs in CMOS. Through direct feedback to the floating gate and a low-leakage switching scheme, all the unwanted factors are eliminated while the output is capable of tracking a pH reaction which occurs at the sensing surface. This is confirmed through measured results of multiple devices of different sensing areas, achieving a mean amplification of 1.28 over all fabricated devices and pH sensitivity of 42.1 mV/pH. The front-end is also capable of compensating for accumulated drift using the designed switching scheme by resetting the floating gate voltage. The circuit has been implemented in a commercially-available 0.35 μm CMOS technology achieving a combined chemical and electrical output RMS noise of 3.1 mV at a power consumption of 848.1 nW which is capable of detecting pH changes as small as 0.06 pH.