Objective To explore the clinical value of the combined measurement of soluble vascular endothelial growth factor receptor-1 （sFlt-1）， lipoprotein-associated phospholipase A2 （Lp-PLA2）， monocyte/high-density lipoprotein cholesterol ratio （MHR）， and intercellular adhesion molecule-1 （ICAM-1） in predicting the severity and prognosis of patients with diabetic foot ulcers （DFU）. Methods A total of 415 patients with DFU who were admitted to Qingdao Central Hospital， University of Health and Rehabilitation Sciences （Qingdao Central Hospital） between January 2022 and January 2025 were selected for this study （DFU group）. Meanwhile， 108 patients with type 2 diabetes mellitus but without DFU （T2DM group） and 108 healthy individuals undergoing physical examinations were recruited from the same hospital （control group）. According to the Wagner classification， the patients with DFU were classified into the grade 1 group （155 cases）， the grade 2 group （127 cases）， the grade 3 group （72 cases）， and the grade 4 group （61 cases）. After a 6-month follow-up during which the prognosis was recorded， the patients were further categorized into 303 cases （good prognosis group） and 112 cases （poor prognosis group） based on their prognosis. The levels of sFlt-1， Lp-PLA2， MHR， and ICAM-1 were compared among the DFU group， the T2DM group， and the control group， as well as among different severity groups. The correlations between the levels of these markers （sFlt-1， Lp-PLA2， MHR， and ICAM-1） and the severity of the disease were analyzed. Additionally， multivariate logistic regression analysis was used to identify the risk factors for poor prognosis in patients with DFU. The predictive value of the combined detection of sFlt-1， Lp-PLA2， MHR， and ICAM-1 for poor prognosis in DFU was analyzed using the receiver operating characteristic curve （ROC）. Results The levels of sFlt-1， Lp-PLA2， MHR， and ICAM-1 in both the DFU group and the T2DM group were higher than those in the control group， and the levels in the DFU group were significantly higher than those in the T2DM group （P < 0.05）. The levels of sFlt-1， Lp-PLA2， MHR， and ICAM-1 increased progressively as the Wagner grades increased （P < 0.05）. The results of the correlation analysis indicated that the levels of sFlt-1， Lp-PLA2， MHR， and ICAM-1 were positively correlated with the severity of the disease （r = 0.531， 0.568， 0.624， 0.615， P < 0.05）. In comparison with the group with a good prognosis， the group with a poor prognosis was older， had higher levels of glycosylated hemoglobin， fasting blood glucose， sFlt-1， Lp-PLA2， monocyte count， MHR， and ICAM - 1， and lower HDL-C （P < 0.05）. The results of the multivariate Logistic regression analysis demonstrated that older age （OR = 1.855， 95%CI： 1.261 - 2.730）， higher glycosylated hemoglobin （OR = 1.719， 95%CI： 1.247 - 2.371）， higher fasting blood glucose （OR = 1.747， 95%CI： 1.237 - 2.467）， higher sFlt - 1 （OR = 1.719， 95%CI： 1.227 - 2.409）， higher Lp-PLA2 （OR = 1.921， 95%CI： 1.321 - 2.794）， higher monocyte count （OR = 1.889， 95% CI 1.249 - 2.856）， higher MHR （OR = 1.624， 95%CI： 1.192 - 2.214）， and higher ICAM-1 （OR = 1.948， 95% CI： 1.203 - 3.156） were all risk factors for a poor prognosis in patients with DFU. High HDL-C （OR = 0.652， 95%CI： 0.490 - 0.869） is a protective factor for a poor prognosis in patients with DFU （all P < 0.05）. The area under the curve （AUC） values for diagnosing the poor prognosis of DFU through the combined detection of soluble fms-like tyrosine kinase-1 （sFlt-1）， lipoprotein-associated phospholipase A2 （Lp-PLA2）， monocyte-to-high-density lipoprotein cholesterol ratio （MHR）， intercellular adhesion molecule-1 （ICAM-1）， and Logistic combined detection were 0.742， 0.815， 0.800， 0.811， 0.827， and 0.899， respectively. Among these， the AUC values of the combined detection of the four indicators and Logistic combined detection were relatively higher. Conclusions The levels of sFlt-1， Lp-PLA2， MHR， and ICAM-1 are closely associated with the severity of DFU. Older age， high glycated hemoglobin， high fasting blood glucose， high sFlt-1， high Lp-PLA2， high monocyte count， high MHR， and high ICAM-1 are all independent risk factors for poor prognosis in DFU patients， while HDL-C is a protective factor for poor prognosis in patients with DFU. The combined detection of sFlt-1， Lp-PLA2， MHR， and ICAM-1 has a higher predictive value than individual indicators and may provide a novel perspective for the prognostic assessment of DFU.