Sn-doped NiO multiroom spheres with unique microreactor morphology were prepared by facile ultrasonic spray pyrolysis of a solution containing tin oxalate, nickel nitrate, and dextrin and subsequent heat treatment. The multiroom structure was formed by phase segregation between the molten metal source and liquidlike dextrin and sequent decomposition of dextrin during spray pyrolysis, which played the dual roles of enhancing gas response and selectivity. The response (resistance ratio) of the Sn-doped NiO multiroom spheres to 1 ppm p-xylene was as high as 65.4 at 300 °C, which was 50.3 and 9.0 times higher than those of pure NiO multiroom spheres and Sn-doped NiO dense spheres, respectively. In addition, the Sn-doped NiO multiroom sensors showed a high selectivity to xylene. The unprecedented high response that enables the sensing of sub-ppm xylene was explained by the high gas accessibility of the multiroom structures and the Sn-doping-induced change in oxygen adsorption as well as the charge carrier concentration, whereas the high xylene selectivity was attributed to the decomposition/re-forming of xylene into smaller or more active species within the unique multiroom structure of Sn-doped NiO microreactors characterized by high catalytic activities. The multiroom oxide spheres can be used as a new and generalized platform to design high-performance gas sensors.