The hole accumulation layer (HAL) configuration of p-type oxides (including Co3O4) in ambient air causes intrinsically low gas response and hinders their promising applications in exhaled gas analysis. Herein, Sn and Ni co-doping has been proposed to trigger the response of chemiresistive Co3O4 sensor toward acetone (biomarker of diabetes). Via incorporating 1 at% Sn and 0.5 at% Ni doping (Co2.95Sn0.03Ni0.02O4), the response to 100 ppm acetone has been boosted ∼2 orders (from 1.24 to 125.6) at 70 °C, the limit of detection (LoD) has been reduced ∼4 times (from 47.9 to 12.4 ppb), the optimal operation temperature has been decreased from 130 °C to ∼70 °C. Various characterizations suggest that co-doping induced abundant surface asymmetric oxygen vacancy defects (Co-□-Ni, Sn-□-Ni), which facilitate the catalytic oxidation of acetone molecules at relatively low operation temperature. In addition to excellent reproducibility and long-term stability, Co2.95Sn0.03Ni0.02O4 sensor could also operate under highly humid air background and reliably detect acetone concentration in exhaled breath at 150 °C, opening the opportunity for the practical application of p-type oxide sensors for diabetes diagnosis.