Transition metal dichalcogenides (TMDCs)/metal oxides are increasingly recognized as competitive sensing materials for detection at room temperature (RT). However, their unsatisfactory properties caused by low sensitivity, slow response, and weak discriminating ability towards interfering gases preclude their further applications in advanced sensing platforms. Herein, a Bi2S3/CuO heterostructure was demonstrated for H2S detection with a highly sensitive rapid response at RT. The Bi2S3/CuO sensor exhibited a greatly improved response (31.2 to 1 ppm H2S) with impressive response kinetics (7.5 s), surpassing that of pure Bi2S3 by a factor of 5 and 17, respectively. Besides, the sensor exhibits outstanding selectivity, repeatability, low detection limit (25 ppb), humidity tolerance and long-term stability. The distinctive enhancement of sensing capabilities primarily results from the synergistic influence of the heterostructure configuration and increased surface-adsorbed oxygen. This strategy of constructing heterostructures between a metal oxide and TMDC provides fundamental insights for developing room-temperature sensors.