Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context. Display omitted •Dimethyl itaconate induces trained immunity in human monocytes•Dimethyl itaconate-induced trained immunity is mediated through glutathione synthesis•Dimethyl itaconate protects mice against infection•Basal plasma itaconate associates with increased human BCG trained immunity capacity Itaconate has broad immunomodulatory properties in mammalian systems and presents various anti-inflammatory properties. Ferreira et al. demonstrate that a derivative of itaconate, dimethyl itaconate, induces trained immunity, thus highlighting the dual role of dimethyl itaconate as a molecule with anti-inflammatory and immune potentiating characteristics.