Oxidative damage results in protein modification and is observed in numerous diseases. Human serum albumin (HSA), the most abundant protein in the plasma, exerts important antioxidant activities to prevent oxidative damage. This paper focuses on the characterization of chemical changes in HSA that are induced by oxidative damage, their relevance to human pathology, and the most recent advances in clinical applications. The antioxidant properties of HSA are largely dependent on Cys-34 and its contribution to the maintenance of intravascular homeostasis, including protecting the vascular endothelium under conditions related to oxidative stress. Recent studies have also evaluated the susceptibility of other important amino acid residues to exposure to free radicals. The findings suggest that a redox change in HSA is related to the oxidation of several amino acid residues by different oxidants. On the other hand, the ratio of the oxidized form to the normal form of albumin (HMA/HNA), which is a function of the redox states of Cys-34, could serve as a useful marker for evaluating systemic redox states, which would be useful for the evaluation of disease progression and therapeutic efficacy. This review provides new insights into our current understanding of the mechanism of HSA oxidation, based on in vitro and in vivo studies.