Human biliverdin-IX alpha reductase (hBVR-A) catalyzes the conversion of biliverdin-IX alpha to bilirubin-IX alpha in the last step of heme degradation and is a key enzyme in regulating a wide range of cellular responses. Though the X-ray structure of hBVR-A is available including cofactor, a crystal structure with a bound substrate would be even more useful as a starting point for protein-structure-based inhibitor design, but none have been reported. The present study employed induced fit docking (IFD) to study the substrate binding modes to hBVR-A of biliverdin-IX alpha and four analogues. The proposed substrate binding modes were examined further by performing molecular dynamics (MD) simulations followed by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The predicted binding free energies for the five biliverdin-IX alpha analogues match well with the relative potency of their reported experimental binding affinities, supporting that the proposed binding modes are reasonable. Furthermore, the ternary complex structure of hBVR-A binding with biliverdin-IX alpha and the electron donor cofactor NADPH obtained from MD simulations was exploited to investigate the catalytic mechanism, by calculating the reaction energy profile using the quantum mechanics/molecular mechanics (QM/MM) method. On the basis of our calculations, the energetically preferred pathway consists of an initial protonation of the pyrrolic nitrogen on the biliverdin substrate followed by hydride transfer to yield the reduction product. This conclusion is consistent with a previous mechanistic study on human biliverdin IX beta reductase (hBVR-B).