It is a significantly difficult problem to obtain the diffusion coefficients by analyzing the concentration profiles in multicomponent melts. Here, based on the Onsager reciprocal relations, we report a new analysis method, which can achieve the diffusion coefficient matrix by fitting the concentration profiles under a given diffusion time. Our method allows us to obtain the interdiffusion coefficient matrix in a multicomponent system via just a single diffusion couple experiment. Thus, it shows obvious merits compared to the previously reported diffusion path method and the square root diffusivity method. As a qualifying example, the four independent interdiffusion coefficients in a Ce–Al–Cu ternary liquid alloy have been derived from the concentration profiles measured by the multi-slice sliding cell technique. It is demonstrated that such a single experiment analysis method shows great potential for wide use in a multicomponent system.