The interaction site of phthalocyanine (Pc) with nitrogen dioxide (NO2) has been characterized using different methods and found to be conflicting. By knowing the interaction site, the Pc molecule can be better customized to improve the gas sensitivity. In this article, the interaction sites of copper phthalocyanine (CuPc) with oxidizing NO2 or with reducing gas (ammonia, NH3) were identified using in situ X-ray absorption spectroscopy (XAS). The sensitivity of CuPc to sub-ppm levels of the tested gases was established in the CuPc chemoresistive gas sensors. The analyte-sensor interaction sites were identified and validated by monitoring the Cu K-edge XAS before and during gas exposure. From the X-ray absorption near-edge structure and its first derivative, a low or lack of axial coordination on the Cu metal center of CuPc is evident. Using the extended X-ray absorption fine structure with molecular orbital information of the involved molecules, the macrocycle interaction between CuPc and NO2 or NH3 was proposed to be the dominant sensing mechanism on CuPc sensors.