Solving the unresolved problem, the pseudo-binary (or quasi-binary or iso-concentration) diffusion couple method has emerged as an elegant and most frequently used research tool for diffusion analysis in multicomponent systems. This is practiced even in a ternary system for the systematic generation of composition-dependent diffusion coefficients, which is otherwise impossible following conventional methods. However, the analysis for the deviations from an “ideal pseudo-binary diffusion profile” is not standardized yet, leading to confusion in the acceptability of the estimated diffusion coefficients. This study explains the logic behind establishing an augmented Darken and Darken-Manning equation schemes suitable for pseudo-binary diffusion profiles considering experimentally produced diffusion profiles and extracted activity profiles of elements. The correct estimation method is demonstrated by producing pseudo-binary profiles up to a six-element system for the first time, depending on the ideal or non-ideal nature of the diffusion profiles. A re-adjustment factor (RAF) concept is introduced, reflecting on the effect of the non-ideality range on estimated diffusion coefficients. This is demonstrated based on several diffusion couple experiments in multiple systems of technological importance that produce different ranges of ideal, near-ideal, minor, and major non-ideal pseudo-binary diffusion profiles. RAF values provide an ultimate guideline for pseudo-binary diffusion analysis in multicomponent systems depending on the extent of non-ideality and composition range of the main diffusing elements. Additionally, the importance of estimating the tracer and intrinsic diffusion coefficients instead of only interdiffusion coefficients (reported mostly) is substantiated by estimating all types of diffusion coefficients when relevant.