Protein A from the bacterium Staphylococcus aureus (SpA) has been widely used as an affinity ligand for purification of immunoglobulin G (IgG). The affinity between SpA and IgG is affected differently by salt and pH, but their molecular mechanisms still remain unclear. In this work, molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area analysis were performed to investigate the salt (NaCl) and pH effects on the affinity between SpA and human IgG1 (hIgG1). It is found that salt and pH affect the interactions of the hot spots of SpA by different mechanisms. In the salt solution, the compensations between helices I and II of SpA as well as between the nonpolar and electrostatic energies make the binding free energy independent of salt concentration. At pH 3.0, the unfavorable electrostatic interactions increase greatly and become the driving force for dissociation of the SpA-hIgG1 complex. They mainly come from the strong electrostatic repulsions between positively charged residues (H137, R146, and K154) of SpA and the positively charged residues of hIgG1. It is considered to be the molecular basis for hIgG1 elution from SpA-based affinity adsorbents at pH 3.0. The dissociation mechanism is then used to refine the binding model of SpA to hIgGl. The model is expected to help design high-affinity peptide ligands of IgG.