Room-temperature optoelectronic gas sensing presents a viable solution for efficient and low-cost NO 2 gas monitoring. Two-dimensional (2D) metal oxychalcogenides, induced by the partial sulfur replacement with oxygen in metal chalcogenide, have been considered to be suitable sensitive materials owing to their excellent long-term stability and complete reversibility. However, the correlation of oxygen-to-sulfur content with gas sensing performances has yet to be known, hindering the optimization process of such an emerging NO 2 gas sensing approach. In this work, we realize 2D ultrathin indium oxysulfide by combining the annealing of bulk In 2 S 3 crystals and subsequently liquid phase exfoliation, while the degree of sulfur replacement with oxygen is controlled by the initial annealing temperature. At an optimum annealing temperature of 800 °C, the sample exhibits an optical bandgap of 2.19 eV and a photoexcited carrier lifetime of 272.82 ns. As a result, it demonstrates a response factor of 7.26 for 126 ppb of NO 2 under blue light illumination at room temperature, while complete reversibility, high selectivity, and excellent long-term stability are also achieved. An extremely low limit-of-detection of 0.0342 ppb is shown, far beyond that of reported room-temperature optoelectronic NO 2 sensors. This work presents the optimization of the implementation of 2D metal oxychalcogenides in NO 2 gas sensing, paving the way to develop next-generation NO 2 monitoring systems.