Although drug-eluting stents (DESs) are mainly coated with biodegradable polymers such as PLGA and PLLA, their acidic degradation products can alter the local microenvironment and affect the homeostasis of adjacent tissue. Previously, we developed anti-inflammatory PLGA-based materials including magnesium hydroxide (MH) to relieve the side effects caused by PLGA degradation. However, the underlying molecular mechanism of its protective effects has not yet been clarified. Here, we demonstrated the pathological mechanism of vascular endothelial activation caused by PLGA by-products. The PLGA by-products accumulated in HCAECs through MCT1, followed by oxidative stress and the activation of the MAPK/NF-κB signaling pathway. Finally, the PLGA by-products increased the expression of VCAM-1 as well as the secretion of proinflammatory cytokines. However, the addition of MH particles significantly diminished the activation of this molecular pathway and the expression of inflammation-related factors induced by acidic PLGA degradation products. Furthermore, Mg2+ released from MH particles restored endothelial function in both intracellular and extracellular spaces. Taken together, MH particles prevent the accumulation of PLGA degradation products in HCAECs, thereby repressing the associated vascular endothelial activation. These findings on the biochemical mechanisms are expected to provide important clues for addressing the safety issues in nearly all biodegradable polymer-based implants.