Herein， we characterize the Toll-like receptor (TLR)-to-NF-κB innate immune pathway of Orbicella faveolata (Of)， which is an ecologically important， disease-susceptible， reef-building coral. As compared to human TLRs， the intracellular TIR domain of Of-TLR is most similar to TLR4， and it can interact in vitro with the human TLR4 adapter MYD88. Treatment of O. faveolata tissue with lipopolysaccharide， a ligand for mammalian TLR4， resulted in gene expression changes consistent with NF-κB pathway mobilization. Biochemical and cell-based assays revealed that Of-NF-κB resembles the mammalian non-canonical NF-κB protein p100 in that C-terminal truncation results in translocation of Of-NF-κB to the nucleus and increases its DNA-binding and transcriptional activation activities. Moreover， human IκB kinase (IKK) and Of-IKK can both phosphorylate conserved residues in Of-NF-κB in vitro and induce C-terminal processing of Of-NF-κB in vivo. These results are the first characterization of TLR-to-NF-κB signaling proteins in an endangered coral， and suggest that these corals have conserved innate immune pathways.