<p>MicroRNAs (miRNAs) have been widely explored in the study and management of lower extremity deep vein thrombosis (LEDVT). However, the function and mechanism of miR-582‐3p in LEDVT remain unclear. The study aimed to explore the expression and regulatory functions of miR-582-3p in LEDVT and Human Umbilical Vein Endothelial Cells (HUVECs). Serum samples from 118 LEDVT patients and 82 healthy controls were collected. RT-qPCR was used to detect the expression levels of miR-582-3p and TFRC in serum and cells. The AUC and logistic analysis were used for the diagnosis and risk prediction of LEDVT. ox-LDL treated HUVECs were used to construct injury cell models. The CCK8, flow cytometry, and ELISA were employed to analyze cell function. Dual-luciferase reporter assays and rescue experiments verified the regulatory relationship between miR-582-3p and TFRC. MiR-582-3p was significantly downregulated in LEDVT patients and in ox-LDL-HUVECs. It was negatively correlated with the levels of D-dimer and TAT III. Additionally, for miR-582-3p, the AUC was 0.870, and it was an independent protective factor. MiR-582-3p mimics promoted the proliferation of ox-LDL-HUVECs, inhibited their apoptosis, and reduced the levels of inflammatory factors (TNF-α, IL-1β, IL-6) and coagulation factors (FXⅢ, TF, PAF). Additionally, miR-582-3p directly targeted TFRC, and overexpression of TFRC reversed the protective effect of miR-582-3p against ox-LDL-induced cellular damage. MiR-582-3p is a potential diagnostic biomarker and independent protective factor for LEDVT. MiR-582-3p regulates endothelial cell function by targeting TFRC, suggesting its potential as a therapeutic target for LEDVT.</p>