Nonmutational mechanisms were recently discovered leading to reversible drug tolerance. Despite the rapid elimination of a majority of tumor cells, a small subpopulation of "'drug-tolerant"' cells remain viable with lethal drug exposure, which may further lead to resistance or tumor relapse. Several signaling pathways are involved in the local or systemic inflammatory responses contributing to drug-induced phenotypic switch. Here, we report that Toll-like receptor 4 (TLR4)-interacting lipid docosahexaenoic acid (DHA) restores the cytotoxic effect of doxorubicin (DOX) in the lipopolysaccharide-treated breast tumor cell line 4T1, preventing the phenotypic switch to drug-tolerant cells, which significantly reduces primary tumor growth and lung metastasis in both 4T1 orthotopic and experimental metastasis models. Importantly, DHA in combination with DOX delays and inhibits tumor recurrence following surgical removal of the primary tumor. Furthermore, the coencapsulation of DHA and DOX in a nanoemulsion significantly prolongs the survival of mice in the postsurgical 4T1 tumor relapse model with significantly reduced systemic toxicity. The synergistic antitumor, antimetastasis, and antirecurrence effects of DHA + DOX combination are likely mediated by attenuating TLR4 activation, thus sensitizing tumor cells to standard chemotherapy.© 2022 The Authors. Published by American Chemical Society.