“One key to one lock” hybrid sensor configuration is rationally designed and demonstrated as a direct effective route for the target-gas-specific, highly sensitive, and promptly responsive chemical gas sensing for room temperature operation in a complex ambient background. The design concept is based on three criteria: (i) quasi-one-dimensional metal oxide nanostructures as the sensing platform which exhibits good electron mobility and chemical and thermal stability; (ii) deep enhancement-mode field-effect transistors (E-mode FETs) with appropriate threshold voltages to suppress the nonspecific sensitivity to all gases (decouple the selectivity and sensitivity away from nanowires); (iii) metal nanoparticle decoration onto the nanostructure surface to introduce the gas specific selectivity and sensitivity to the sensing platform. In this work, using Mg-doped In2O3 nanowire E-mode FET sensor arrays decorated with various discrete metal nanoparticles (i.e., Au, Ag, and Pt) as illustrative prototypes here further confirms the feasibility of this design. Particularly, the Au decorated sensor arrays exhibit more than 3 orders of magnitude response to the exposure of 100 ppm CO among a mixture of gases at room temperature. The corresponding response time and detection limit are as low as ∼4 s and ∼500 ppb, respectively. All of these could have important implications for this “one key to one lock” hybrid sensor configuration which potentially open up a rational avenue to the design of advanced-generation chemical sensors with unprecedented selectivity and sensitivity.