Regulator of G protein signaling 10 (RGS10) is a member of the superfamily of RGS proteins that canonically act as GTPase activating proteins (GAPs), which accelerate GTP hydrolysis on the G-protein α subunits and result in termination of signaling pathways downstream of G protein-coupled receptors. Independent of its canonical function, RGS10 has emerged as an anti-inflammatory protein by inhibiting LPS-mediated NF-κB activation and expression of inflammatory cytokines, in particular TNFα. Although RGS10 is abundantly expressed in resting macrophages, previous studies have shown that RGS10 expression is suppressed in macrophages following toll-like receptor 4 (TLR4) activation by LPS. However, the molecular mechanism by which LPS induces Rgs10 silencing has not been clearly defined. The goal of the current study was to determine whether LPS silences Rgs10 expression through an NF-κB mediated proinflammatory mechanism in pulmonary macrophages, a unique type of innate immune cells. We demonstrate that Rgs10 transcript and RGS10 protein levels are suppressed upon LPS treatment in MHS alveolar macrophage cell line. We show that pharmacological inhibition of PKC-δ/ NF-κB/p300 (NF-κB co-activator)/TNFα signaling cascade and the activities of HDAC enzymes block LPS-induced silencing of Rgs10 in MHS cells as well as microglial BV2 cells. Further, loss of RGS10 by using CRISPR/Cas9 amplifies NF-κB phosphorylation and inflammatory genes expression following LPS treatment in MHS cells. Together, our findings strongly provide critical insight into the molecular mechanism underlying RGS10 suppression by LPS in macrophages.