<p>B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy commonly found in pediatric patients. This study aims to screen hub genes in B-ALL and elucidate the role of peroxiredoxin 1 (<i>PRDX1</i>) in the modulation of ferroptosis. Bioinformatics analyses were conducted to identify pivotal genes in the GSE17703 and GSE48558 datasets. The biological effects of <i>PRDX1</i> deletion in B-ALL cells and the xenograft tumor were evaluated using a series of functional assays. Ferroptosis was induced in B-ALL cells using erastin. Transcriptome sequencing was performed on Nalm-6 cells before and after <i>PRDX1</i> knockdown. Forskolin was employed to explore the role of <i>PRDX1</i> in the cyclic adenosine monophosphate (cAMP) pathway. Four pivotal genes were identified, with two genes upregulated and two downregulated. Depletion of <i>PRDX1</i> suppressed the proliferative, migratory, and invasive abilities of B-ALL cells, whereas <i>PRDX1</i> overexpression exerted the opposite effects. <i>PRDX1</i> silencing promoted erastin-induced ferroptosis, including elevated levels of COX2, ACSL4, ferrous ions, ROS, and MDA, while reducing GPX4, GSH, and SOD levels. <i>PRDX</i>1 knockdown further reduced the viability of B-ALL cells treated with the ferroptosis activator ML210, and treatment with the ferroptosis inhibitor liproxstatin-1 significantly reversed the suppressive effect of <i>PRDX1</i> knockdown on xenograft tumor growth. Mechanically, <i>PRDX1</i> deletion triggered ferroptosis in B-ALL cells by inhibiting the cAMP pathway. <i>PRDX1</i> deficiency modulates ferroptosis in B-ALL cells by blocking the cAMP pathway, which offer a novel perspective on the pathogenesis of B-ALL.</p>