Sensitivity and selectivity are important factors for Tl₂O monolayer to be the sensitive material. In this work, the sensing performance of NO₂ on pure and X-Tl₂O (X = In, Cd, Y, Pb, Ga, Si) sheets has been detailed investigated by means of DFT. The results show that the doped systems have a better sensing performance for NO₂ and it is most evident in the In-Tl₂O substrate. And In-Tl₂O has a unique response to NO₂ with appropriate adsorption energy (−1.79 eV) and charge transfer (−0.51 e) which are far more than B-C₃N (−1.15 eV, 0.44 e). Besides, although In-Tl₂O monolayer and SO₂ have formed the chemical bond, the adsorption effect of NO₂ on the substrate hardly changes when the co-adsorption of SO₂ and NO₂ occurs on it. In addition, the reflectivity and optical absorption of the gas/In-Tl₂O (gas = NO, NO₂ and SO₂) adsorption system are calculated, and the results indicate optical absorption and reflectivity of NO₂/In-Tl₂O system are all far greater than that of other systems in the visible and near infrared regions. So it is easy to be distinguished by infrared detection. These all show that the In-Tl₂O is an excellent sensing material for NO₂ detection.