Acute myeloid leukemia (AML) remains clinically challenging due to its molecular heterogeneity and poor outcomes, highlighting the urgent need for novel biomarkers and therapeutic targets. This study aims to identify and characterize the role of leucine-rich α-2-glycoprotein 1 (LRG1) in AML, evaluating its potential as both a prognostic biomarker and a therapeutic target. We conducted an integrated basic and clinical investigation of LRG1 in AML. Methods included analysis of LRG1 expression in patient samples versus controls and pre- versus post-treatment, assessment of its clinical correlations with mutations and subtypes, and evaluation of its prognostic impact. Functional validation was performed using LRG1 knockdown models to assess effects on colony formation, apoptosis, and differentiation. Single-cell RNA profiling was utilized to identify LRG1-enriched cell populations and explore its role in microenvironmental crosstalk. Integrated analysis revealed significantly elevated LRG1 expression in AML patients compared to controls (P<0.001), with levels decreasing post-treatment (P<0.001). High LRG1 expression correlated with FLT3 mutations (P<0.01), M3-M5 AML subtypes (M0&M1&M2 VS M3, P<0.001; M0&M1&M2 VS M4, P<0.01; M0&M1&M2 VS M5, P<0.001; M3 VS M5, P<0.05; M4 VS M5, P<0.05), and worse survival (P<0.01). Functionally, LRG1 knockdown impaired colony formation (P<0.001), increased apoptosis (P<0.001), and disrupted differentiation (P<0.01). Single-cell profiling identified LRG1 enrichment in hematopoietic stem and progenitor cells (HSPCs) and myeloid progenitors, where it facilitated microenvironmental crosstalk via Macrophage Migration Inhibitory Factor (MIF), Galactoside-binding lectin (GALECTIN), and Cyclophilin A (CypA) signals. Our findings establish LRG1 as a robust prognostic biomarker and a key functional regulator of AML maintenance through myeloid progenitor dysregulation, presenting it as a promising target for new therapeutic strategies.