This paper reports for the first time, smart 3D-Extended-Metal-Gate Ion-Sensitive-Field-Effect-Transistors (3D-EMG-ISFETs), with unique figures of merit: (i) extremely-low-power (down to a record value of 2 pW per sensor under excellent linearity), (ii) all CMOS integrated, (iii) high performance pH and multi-ion (Na+, K+, Ca2+) sensing, and, (iv) uniquely low cross sensitivity experimentally proven. Detailed electrical DC and dynamic characterizations show excellent sensitivities (56.8 mV/pH, -58mV/dec for Na+, -49.5 mV/dec for K+, and -21.9 mV/dec for Ca2+) and high selectivity of each ion sensor against 4 different ions that usually coexist in biofluids, all achieved on same CMOS die. Furthermore, unprecedented results show that the threshold voltage (V-th) variability of such CMOS ISFET is reduced by 78 times. We report a V-th drift rate in liquid conditions of 0.67 mV/h, decreased by one order of magnitude compared to other state of the art CMOS ISFETs. Overall, the reported experimental achievements, supported by SPICE calibrated behavioral model simulations results shown in this paper, are expected to greatly enhance the predictability of high performance multi-analyte ISFETs, which is a big step towards ISFET sensor system mass production.