Soy protein has been extracted and differently treated to yield products of diverse desirable characteristics. Generally, synthetic chemicals (NaOH and HCl) are used to extract the protein from n-hexane-defatted soy flour (DF). Some researchers have tried to extract it from full-fat flour (FF) using natural chemicals (NC) in response to the ever-increasing consumer preference for naturally processed foods. The effects of these chemicals on the structure of the resultant protein product are not known. This study examined oxidative and structural modification effects of NC and SC as they interact with proteins in the DF and FF systems. Significant differences (p < 0.01) were observed in all samples in lipoxygenase activity, degree of oxidation, free and total sufhydryl content and intrinsic fluorescence, which indicated increased structural changes in the FF-based samples as compared to those prepared from DF. Circular dichroism spectroscopy showed existence of α-helices and β-sheets protein secondary structures. However, DF samples showed increase in unordered structural conformation changes than the FF sample. Surface hydrophobicity and size exclusion chromatography results were more related to the extraction chemicals than the type of flour used, with samples prepared with SC showing an increase. That’s, the use of natural and synthetic protein extraction chemicals from FF and DF have different effects on the structure and degree of oxidation of the resultant proteins.