Endovascular aortic repair (EVAR) is often followed by aneurysm recurrence. Alginate oligosaccharide (AOS) has potential antitumor properties as a natural product while the related mechanisms remain unclear. Toll-like receptor (TLR) signaling is associated with inflammatory activity of aneurysm and may be affected by miR-29b. Thus, inhibitory function of AOS on aneurysms was explored by measuring the important molecules in TLR4 signaling. After EVAR, a total of 248 aortic aneurysm patients were recruited and randomly assigned into two groups: AOS group (AG, oral administration 10-mg AOS daily) and control group (CG, placebo daily). The size of residual aneurysms, aneurysm recurrence, and side effects were investigated. Aneurysm recurrence was determined by Kaplan–Meier analysis. After 2 years, eight and two patients died in the CG and AG, respectively. The sizes of residual aneurysms were significantly larger in the CG than in the AG ( P<0.05). The incidence of aneurysm recurrence was also significantly higher in the CG than in the AG ( P<0.05). AOS treatment reduced the levels of miR-29b, TLR4, mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappa B), interleukin 1 (IL-1) beta, and interleukin 6 (IL-6). Overexpression and silence of miR-29b increased and reduced the level of TLR4, phospho-p65 NF-kappa B, phospho-p38 MAPK, IL-1 beta, and IL-6. Spearman’s rank correlation analysis shows that the level of miR-29b is positively related to the levels of TLR4, NF-kappa B, IL-1 beta, and IL-6 ( P<0.05). Thus, AOS represses aneurysm recurrence by indirectly affecting TLR signaling via miR-29b.