Macrophages can adopt an anti-inflammatory phenotype through exposure to TLR ligands together with immune complexes (IC). However, a thorough investigation of this phenotype in human macrophages has not yet been performed. In this work, we sought to characterize IC-induced regulatory activation in primary human macrophages (R-Mφ-IC). Analysis of the transcriptome and secretome revealed broad suppression of inflammatory molecules, and an upregulation of molecules involved in angiogenesis and the resolution of inflammation. RNAscope and flow cytometry analysis identified MMP-10 and DC-STAMP, among others, as potential biomarkers for this activation state. Pathway analysis predicted the activation of the Akt and ERK signaling pathways, which further studies confirmed were activated in these cells. Inhibition of Akt and ERK led to a suppression of R-Mφ-IC gene transcription, with Akt inhibition having a greater effect. Since GSK3 is a direct substrate of Akt, activation of this kinase was also investigated. The addition of IC to cells stimulated with lipopolysaccharide (LPS) significantly prevented the entry of GSK3 into the nucleus, while small-molecule inhibition of GSK3 phenocopied IC co-stimulation. To determine if GSK3 inhibition had anti-inflammatory activity, mice were injected intraperitoneally with macrophages treated with LPS and GSK3β-specific inhibitor. Compared to mice injected with macrophages stimulated only with LPS, the mice in the test group were slightly protected from lethal endotoxemia, but these results were not statistically significant (p-value = 0.063). Together these data are consistent with an anti-inflammatory role for Fc receptor cross-linking, and highlight the importance of the Akt/GSK3 signaling pathway in this activity.