Two-dimensional (2D) MoS₂ with appealing physical properties is a promising candidate for next-generation electronic and optoelectronic devices, where the ultrathin MoS₂ is usually laid on or gated by a dielectric oxide layer. The oxide/MoS₂ interfaces widely existing in these devices have significant impacts on the carrier transport of the MoS₂ channel by diverse interface interactions. Artificial design of the oxide/MoS₂ interfaces would provide an effective way to break through the performance limit of the 2D devices but has yet been well explored. Here, we report a high-performance MoS₂-based phototransistor with an enhanced photoresponse by interfacing few-layer MoS₂ with an ultrathin TiO₂ layer. The TiO₂ is deposited on MoS₂ through the oxidation of an e-beam-evaporated ultrathin Ti layer. Upon a visible-light illumination, the fabricated TiO₂/MoS₂ phototransistor exhibits a responsivity of up to 2,199 A/W at a gate voltage of 60 V and a detectivity of up to 1.67 × 10¹³ Jones at a zero-gate voltage under a power density of 23.2 μW/mm². These values are 4.0 and 4.2 times those of the pure MoS₂ phototransistor. The significantly enhanced photoresponse of TiO₂/MoS₂ device can be attributed to both interface charge transfer and photogating effects. Our results not only provide valuable insights into the interactions at TiO₂/MoS₂ interface, but also may inspire new approach to develop other novel optoelectronic devices based on 2D layered materials.