Sensors based on organic field effect transistors have attracted extensive interests, but most sensors are applied to a single analyte detection. Herein, a facile strategy was proposed to optimize the growth of active layers by regulating the thickness of vanadyl-phthalocyanine (VOPc) films and carrying out the thermal annealing. Thanks to the improved film morphology and crystal properties, the carrier mobility of transistors reached 0.15 cm2V−1s−1, humidity and nitrogen dioxide (NO2) induced multi-parameter response of transistors could be considered as an efficient sensing approach. The sensitivity of threshold voltage reached 0.59 V/% RH ranging from 42%−82% RH. In addition, the gas sensing performance was systematically studied. Sensors based on 10 nm VOPc films achieved a 4710% response to 10 ppm NO2 gas, with a theoretical limit of detection down to 125.2 ppb, and the response current was improved by two orders of magnitude under the amplification effect of transistor. The obtained gas sensors also exhibited high repeatability after being stored at 90% ambient humidity. It was concluded that different charge carrier transfer mechanism in moisture and NO2 gas provided a simple idea for tunable applications of phthalocyanine-based transistors.