Significance Obesity-associated metaflammation is an emerging disease, in which proinflammatory macrophages play a decisive role. Here, we identified the soluble mannose receptor (sMR) as a regulator of metaflammation and demonstrated increased levels of sMR in obese mice and humans. Additionally, we identified that increased sMR directly binds to CD45 on macrophages, inhibiting its activity and inducing inflammatory macrophage activation via the Akt/NF-κB pathway. Consequently, increased sMR levels induced inflammatory activation of metabolic tissue macrophages and aggravation of whole-body metabolic homeostasis. These data identify the MR as a regulator of macrophage activation and offer perspectives for therapeutic approaches for the treatment of metaflammation.