Abstract: Objective To explore the expression of high mobility group protein A1 (HMGA1) and peroxiredoxin 1 (PRDX1) in the serum of patients with polycystic ovary syndrome (PCOS) and its clinical significance. Methods A total of 164 PCOS patients who were admitted to the Affiliated Hospital of Xuzhou Medical University from August 2023 to June 2024 were selected as a study group. Another 187 healthy women undergoing routine physical examinations during the same period were chosen as a control group. The study group was further subdivided by body mass index (BMI) into an obese group (BMI≥28 kg/m²,n=70) and a non-obese group (BMI<28 kg/m², n=94). Furthermore, 104 patients from the study group with BMI≥24 kg/m² were selected as a weight-loss group, who were reassessed after two months of weight management. Serum HMGA1 and PRDX1 levels were measured using enzyme-linked immunosorbent assay, and their correlation with clinical data was analyzed. The diagnostic value of serum HMGA1 and PRDX1 levels for PCOS was assessed through receiver operating characteristic (ROC) curve analysis. Results The serum HMGA1 levels in the study group were significantly lower than those in the control group, while PRDX1 levels were significantly higher (P<0.001). In the obese group, serum HMGA1 levels were significantly lower and PRDX1 levels significantly higher than those in the non-obese group (P<0.001). After two months of weight loss intervention, HMGA1 levels in the weight-loss group were higher than those before weight loss, while PRDX1 levels were lower (P<0.05). Pearson correlation analysis indicated a positive correlation between PRDX1 levels and BMI, anti-Müllerian hormone (AMH), luteinizing hormone (LH), homeostasis model assessment of insulin resistance (HOMA-IR), and triglycerides (TG) (r>0, P<0.05) and a negative correlation between HMGA1 levels and BMI, AMH, LH, HOMA-IR, and testosterone (T) (r<0, P<0.05). ROC curve analysis indicated that the area under the curve (AUC) for HMGA1 and PRDX1 alone were 0.78 and 0.79, respectively, while the combined detection yielded an AUC of 0.82, with statistical significance (P<0.001). Conclusions Serum HMGA1 levels decrease and PRDX1 levels increase in PCOS patients, and both are associated with glucose and lipid metabolism indicators. Combined detection of HMGA1 and PRDX1 has higher diagnostic value for PCOS.