Mg-based alloys might be ideal biomaterials in clinical applications owing to favorable mechanical properties, biodegradability, biocompatibility, and especially their anti-inflammatory properties. However, the precise signaling mechanism underlying the inhibition of inflammation by Mg-based alloys has not been elucidated. Here, we investigated the effects of a Mg-2.1Nd-0.2Zn-0.5Zr alloy (denoted as JDBM) on lipopolysaccharide (LPS)-induced macrophages. THP-1 cell-derived macrophages were cultured on JDBM, Ti−6Al−4V alloy (Ti), 15% extract of JDBM, and 7.5 mM of MgCl₂ for 1 h before the addition of LPS for an indicated time; the experiments included negative and positive controls. Our results showed JDBM, extract, and MgCl₂ could decrease LPS-induced tumor necrosis factor (TNF) and interleukin (IL)-6 expression. However, there were no morphologic changes in macrophages on Ti or JDBM. Mechanically, extract and MgCl₂ downregulated the expression of toll-like receptor (TLR)-4 and MYD88 compared with the positive control and inhibited LPS-induced nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by inactivation of the phosphorylation of IKK-α/β, IKβ-α, P65, P38, and JNK. Additionally, the LPS-induced reactive oxygen species (ROS) expression was also decreased by extract and MgCl₂. Interestingly, the expression of LPS-induced TNF and IL-6 could be recovered by knocking down TRPM7 of macrophages, in the presence of extract or MgCl₂. Mechanically, the activities of AKT and AKT1 were increased by extract or MgCl₂ with LPS and were blocked by a PI3K inhibitor, whereas siRNA TRPM7 inhibited only AKT1. Together, our results demonstrated the degradation products of Mg-based alloy, especially magnesium, and resolved inflammation by activation of the TRPM7–PI3K–AKT1 signaling pathway, which may be a potential advantage or target to promote biodegradable Mg-based alloy applications.