Nanoparticles (NPs) have been widely studied and applied in medical and pharmaceutical fields. When NPs enter the environment, they are covered with protein molecules to form the so-called "protein corona". Because NPs and proteins are comparable in size, the shape of NPs has a significant impact on NP-protein interactions. Although NPs of various shapes have been synthesized, how the shape of NPs affects the protein corona is poorly understood, and little is known about the underlying molecular mechanism. In the present study, we synthesized spherical, football-shaped, and rod-shaped semiconductor nanocrystals (SNCs) as model NPs and compared their interaction with human serum albumin (HSA) using fluorescence correlation spectroscopy, fluorescence quenching, Fourier-transform infrared spectroscopy, and thermodynamic analysis. Based on the binding enthalpy and entropy and secondary structural changes of HSA, with the help of hydrodynamic diameter changes of SNCs, we concluded that HSA adopts a conformation or orientation that is appropriate for the local curvature of SNCs. This study demonstrates the effect of NP shape on their interaction with proteins and provides a mechanistic perspective.