Toll-like receptors (TLRs) play a critical role in the innate immune response against pathogens. Each TLR recognizes specific pathogen-associated molecular patterns and then activates adaptor protein MyD88 or TRIF-assembled signaling complex to produce immune mediators, including inflammatory cytokines and type I IFNs. Although the activation of TLR is important for host defense, its uncontrolled activation can damage to the host. During the past decade, numerous studies have demonstrated that GSK3β is a key regulator of inflammatory cytokine production in MyD88-mediated TLR signaling via TLR2 and TLR4. Recently, GSK3β has also been implicated in TRIF-dependent signaling pathway via TLR3. In this review, we describe current advances on the regulatory role of GSK3β in immune responses associated with various TLRs. A better understating of the role of GSK3β in TLR signaling might lead to more effective anti-inflammatory interventions.