The interaction of covellite hexagonal phase of copper sulphide nanoparticles (CuS NPs) with bovine serum albumin (BSA) was examined systematically by using fluorescence, UV-visible, circular dichroism (CD), Fourier transform infrared (FTIR), dynamic light scattering (DLS) and molecular modelling techniques. Electrochemical method was studied to further confirm the interaction of BSA with CuS NPs. The results of fluorescence studies demonstrated that fluorescence of BSA was quenched by CuS NPs via a static quenching mechanism. The negative values of thermodynamic parameters (Delta G, Delta H and Delta S) indicated that the binding process is spontaneous, exothermic and van der Waals force or hydrogen bonding plays major roles in the interaction of CuS NPs with BSA. The interaction of CuS NPs with Trp residue was established by synchronous studies, and competitive binding studies revealed that Trp-212 of subdomain IIA was involved in the interaction with these nanoparticles. Further, the efficiency of energy transferred and the distance between fluorophore (BSA) and acceptor (CuS NPs) were calculated using Forster's resonance energy transfer theory. The results of UV-visible, CD, FTIR and DLS revealed that the CuS NPs interact with BSA by inducing the conformational changes in secondary structure and reducing the alpha-helix content of BSA. Molecular modelling studies suggested that CuS NPs bind to site I of sub domain IIA of BSA. The results of spectroscopic and molecular docking studies were complimented by the electrochemical techniques.