Toll-like receptor 4 (TLR4) plays a vital role in the innate immune response, but its overactivation has been associated with several diseases, such as aggressive progression of triple-negative breast cancer (TNBC). As a result, inhibiting TLR4 has emerged as a potential therapeutic strategy for this challenging breast cancer subtype. This review summarizes recent advancements in the development of small-molecule TLR4 antagonists to suppress TNBC growth, metastasis, and chemotherapy resistance. We also examine their potential in managing cancer-related complications and propose future directions for their application in TNBC therapy.