Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRs) have been identified as crucial regulators of cardiovascular pathology, and represent novel therapeutic targets for potential inhibition of AAA expansion. By using microarray as well as qrt-PCR techniques, we identified miRs -21 and -29b as key modulators of proliferation, apoptosis, and fibrosis in developing AAAs in two murine models: the porcine-pancreatic-elastase (PPE) model, and the angiotensin II-infusion ApoE-/- mouse model. miR-21 increased with AAA development, and substantially decreased expression of phosphatase and tensin homolog (PTEN) during aneurysm development in both experimental models, resulting in increased levels of p-AKT, a pathway known to exert pro-proliferative and anti-apoptotic effects in various cell types. Increases in Col1a1, Col3a1, Col5a1, and Eln with AAA development were accompanied by decreased miR-29b in both models. In vivo administration of a locked-nucleic-acid (LNA) antagomiR against miR-29b greatly increased collagen gene expression, leading to an early fibrotic response in the abdominal aortic wall (vs. scrambled-control-miR), and resulting in a significant reduction of abdominal aortic diameter progression over time in our murine AAA models. Overexpression of miR-21 using a lentiviral vector inhibited as well AAA expansion by increasing proliferation and decreasing apoptosis, mainly in vascular smooth muscle cells. A similar pattern of miR-21 and miR-29b expression, as well as their target gene regulation was observed in human aortic tissue samples from patients undergoing surgical AAA repair when compared with infra-renal aortic tissue samples from organ donor controls. Regulation of the identified miRs and their target genes represent a potential new therapy in limiting AAA disease progression and protection from rupture.