High-fat, high-sugar (HFHS) meals cause acute postprandial metabolic and oxidative stress, and the capacity to buffer this challenge is increasingly recognised as relevant to cardiometabolic health(1). Blueberries, a rich source of anthocyanins, have shown postprandial metabolic benefits(2), yet their acute effects on the human plasma metabolome during an HFHS meal remain to be fully elucidated. In a double-blind, randomised crossover study (Australian New Zealand Clinical Trials Registry #ACTRN12624001039572), 12 healthy males (age 29.3 ± 2.1 years, BMI 23.9 ± 2.3 kg/m2) consumed an HFHS meal (41% carbohydrate, 42% fat, 17% protein) alone or with freeze-dried blueberry powder. Two blueberry doses (15 g and 30 g; equivalent to ~85 g and ~170 g fresh blueberries) were used to evaluate dose-dependent effects. Plasma samples were collected hourly during fasting and postprandial periods from -120 to 360 min. Metabolites were identified using untargeted hydrophilic interaction ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (HILIC-UHPLC-HRMS), yielding a total of 1757 putatively annotated metabolites. Meal, time, and their interaction (meal × time) were tested using linear mixed models with false discovery rate (FDR) correction, and dose dependence was assessed using polynomial contrasts. Blueberry co-ingestion with the HFHS meal produced a robust, dose-dependent postprandial signature, with 515 metabolites differing between meals, and 19 metabolites showing a significant meal × time interaction (q < 0.05). Dose-dependent metabolites included blueberry (poly)phenol conjugates (ferulic acid 4-sulfate, caffeic acid 3-sulfate, quinic acid; q < 1 × 10-7) and gut microbial catabolites detected in the late postprandial phase (hippuric acid; 5'-(3',4'-dihydroxyphenyl)-γ-valerolactone sulfate) (q < 0.05). Beyond these blueberry-derived (poly)phenolic metabolites, a smaller set of endogenous metabolites decreased dose-dependently in the late postprandial phase (240-360 min) (q < 0.05). These metabolites included markers of oxidative and cellular stress, such as L-homocitrulline (an oxidised metabolite of lysine and product of myeloperoxidase action), 1-methylhypoxanthine (a purine catabolite of xanthine-oxidase activity), and pseudouridine (a stress-induced RNA nucleotide), alongside amino acid and dipeptide metabolites (isoleucine-proline, acetylcarnosine, 2-keto-glutaramic acid). The reduction in these stress markers after meals with blueberries compared with the HFHS meal was consistent with an attenuated oxidative and cellular stress response in the late postprandial phase. In conclusion, freeze-dried blueberry powder dose-dependently reshaped the postprandial plasma metabolome and reduced stress-related metabolites, thereby identifying candidate mechanisms through which blueberries may influence the acute metabolic response to an unhealthy meal.