Toluene is one of the harmful volatile organic compounds (VOCs) for both human health and environments. Thus, to prevent the hazardous effect of toluene, fast detection at an early stage is needed. CuO shows the merit for a wide range responsivity to VOCs but suffers from small response value, slow response/recovery speeds, and low durability. Herein, we report a facile preparation of CuO/Ti3C2Tx MXene hybrids via electrostatic self-assembly. The CuO nanoparticles (∼7 nm) were uniformly dispersed on the surface and the interlayers of the Ti3C2Tx MXene, forming hybrid heterostructures. The CuO/Ti3C2Tx MXene exhibited the improved toluene gas sensing response (Rg/Ra) of 11.4, which is nearly 5 times higher than that of the pristine CuO nanoparticles (2.3) to 50 ppm of toluene at 250 °C. Due to the different work function (Φ), the Schottky junction was established at the interface of CuO/Ti3C2Tx MXene, acting as a hole trapping region (HTR) at the Ti3C2Tx MXene side. Compared to other hybrid 2D materials such as MoS2 and rGO, which possess a higher work function, the CuO/Ti3C2Tx MXene maintained better toluene sensing performance. Thus, the work function is critical for designing a high sensing performance of hybrid metal oxides/2D materials. The hybridization of CuO with Ti3C2Tx MXene improved not only enhancement of the response time but also the selectivity and the responses (270 s) and recovery times (10 s) compared with those of CuO, due to high conductivity of the metallic phase in Ti3C2Tx MXene. Such excellent performance showed the promising applications of metal oxides/2D hybrid materials for VOCs gas sensing.