Toll-like receptors (TLRs) induce innate immune responses recognizing conserved microbial structural molecules. All TLR signaling pathways culminate in the activation of nuclear factor-${kappa}B$ (NF-${kappa}B$). The activation of NF-${kappa}B$ leads to the induction of inflammatory gene products such as cyclooxygenase-2 (COX-2). Guggul has been used for centuries to treat a variety of diseases. Guggulstreone, one of the active ingredients in guggul, has been used to treat many chronic diseases. However, the mechanism as to how guggulsterone mediate the health effects is largely unknown. Here, we report biochemical evidence that guggulsterone inhibits the NF-${kappa}B$ activation and COX-2 expression induced by TLR2, TLR3, and TLR4 agonists. Guggulsterone also inhibits the NF-${kappa}B$ activation induced by downstream signaling components of TLRs, myeloid differential factor 88 (MyD88), $I{kappa}B$ kinase ${eta}$ ($IKK{eta}$), and p65. These results imply that guggulsterone can modulate the immune responses regulated by TLR signaling pathways.