Abstract   Aeromonas hydrophila has been implicated in extra-intestinal infection and diarrhoea in humans. Targetting unique effectors of bacterial pathogens is considered a powerful strategy for drug design against bacterial variations to drug resistance. The two-component bacterial system involving sensor histidine kinase (SHK) and its response regulators is considered a lucrative target for drug design. This is the first report describing a three-dimensional (3D) structure for SHK of A. hydrophila. The model was constructed by homology modelling using the X-ray structure of PleD—a response regulator—in conjunction with cdiGMP (PDB code 1W25) and HemAT sensor domain (PDB code 1OR4)—a globin coupled sensor. A combination of homology modelling methodology and molecular dynamics (MD) simulations was applied to obtain a reasonable structure to understand the dynamic behaviour of SHK. Homology modelling was performed using MODELLER9v2 software. The structure was relaxed to eliminate bad atomic contacts. The final model obtained by molecular mechanics and dynamics methods was assessed using PROCHECK and VERIFY 3D graph, which confirmed that the final refined model is reliable. Until complete biochemical and structural data of SHK are determined by experimental means, this model can serve as a valuable reference for characterising the protein and could be explored for drug targetting by design of suitable inhibitors.