Wide bandgap gallium nitride (GaN)-based devices have attracted a lot of attention in optoelectronics, power electronics, and sensing applications. AlGaN/GaN based sensors, featuring high-density and high-mobility two-dimensional electron gas (2DEG), have been demonstrated to be effective chemical sensors and biosensors in the liquid environment. One of the key factors limiting the wide adoption of the AlGaN/GaN liquid sensor is the package reliability issue. In this paper, the reliability of three types of sensor packaging materials (SiO2/Si3N4, PI, and SiO2/Si3N4/PI) on top of 5-μm metal are tested in Phosphate buffer saline (PBS) solution. By analyzing the I-V characteristics, it is found that the leakage currents within different regimes follow distinct leakage models, whereby the key factors limiting the leakage current are identified. Moreover, the physical mechanisms of the package failure are illustrated. The failure of the SiO2/Si3N4 package is due to its porous structure such that ions in the solution can penetrate into the packaging material and reduce its resistivity. The failure of the PI package at a relatively low voltage (<3 V) is mainly due to the poor adhesion of PI to the AlGaN surface such that the solution can reach the electrode by the “lateral drilling” effect. The SiO2/Si3N4/PI package achieves less than 10 μA leakage current at 5 V voltage stress because it combines the advantages of the SiO2/Si3N4 and the PI packages. The analysis in this work can provide guidelines for the design and failure mechanism analysis of packaging materials.