The precise monitoring of H2S has aroused immense research interest in the biological and biomedical fields since it is exposed as a third endogenous gasotransmitter. Hence, there is an urgent requisite to explore an ultrasensitive and economical H2S detection system. Herein, we report a simple strategy to configure an extremely sensitive electrochemical sensor with a 2D nanosheet-shaped layered double hydroxide (LDH) wrapped carbon nanotubes (CNTs) nanohybrid (CNTs@LDH), where a series of CNTs@CuMn-LDH nanohybrids with varied amounts of LDH nanosheets grafted on a conductive CNTs backbone has been synthesized via a facile coprecipitation approach. Taking advantage of the unique core-shell structure, the integrated electrochemically active CuMn-LDH nanosheets on the conductive CNTs scaffold, the maximum interfacial collaboration, and the superior specific surface area with a plethora of surface active sites and ultrathin LDH layers, the as-prepared CNTs@CuMn-LDH nanoarchitectures have exhibited superb electrocatalytic activity toward H2S oxidation. Under the optimum conditions, the electrochemical sensor based on the CNTs@CuMn-LDH nanohybrid shows remarkable sensing performances for H2S determination in terms of a wide linear range and a low detection limit of 0.3 nM (S/N = 3), high selectivity, reproducibility, and durability. With marvelous efficiency achieved, the proposed sensing platform has been practically used in in situ detection of abiotic H2S efflux produced by sulfate reducing bacteria and real-time in vitro tracking of H2S concentrations from live cells after being excreted by a stimulator which in turn might serve as early diseases diagnosis. Thus, our core-shell hybrid nanoarchitectures fabricated via structural integration strategy will open new horizons in material synthesis, biosensing systems, and clinical chemistry.