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Objective: While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods: Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant‐based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke‐associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio‐weighted mediation was used to determine whether metabolites mediated the association between a plant‐based diet and stroke risk. Results: Metabolites associated with a plant‐based diet included the gut metabolite indole‐3‐propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10−6), guanosine (β = −0.13, 95% CI [−0.19, −0.07], p = 6.48 × 10−5), gluconic acid (β = −0.11, 95% CI [−0.18, −0.04], p = 2.06 × 10−3), and C7 carnitine (β = −0.16, 95% CI [−0.24, −0.09], p = 4.14 × 10−5). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10−3), gluconic acid (35.7%, p = 2.28 × 10−3), and C7 carnitine (26.2%, p = 1.88 × 10−2) as mediators linking a plant‐based diet to reduced stroke risk. Interpretation: A subset of diet‐related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500–510 [ABSTRACT FROM AUTHOR]