A dietary shift in favor of plant protein (PP) sources over animal protein (AP) sources is encouraged both for environmental and health reasons, especially for limiting cardiometabolic risk. We aimed at characterizing the metabolic reorientations induced by a reasonable dietary shift from AP to PP sources in a population at cardiometabolic risk. We conducted a 1-month cross-over randomized controlled trial (NCT04236518) in 19 healthy overweight men with cardiometabolic risk, following 2 controlled iso-caloric diets (lunch and dinner provided) containing predominantly AP (66% AP:34% PP) or PP sources (37% AP:63% PP). Plasma metabolome (untargeted LC-MS) was assessed at the fasted state every 2 weeks and after each intervention period (AP or PP diet) during 6 hours following a high-fat challenge meal (900kcal, lipids=80%E). Classical clinical endpoints and vascular function (brachial artery flow-mediated dilatation) were measured at fasted and fed state. Multivariate (LiMM-PCA) and univariate analyses were performed on metabolomics data while other variables were analyzed with mixed models. Plasma metabolome, but not glucose and lipid homeostasis nor vascular function, significantly differed between PP and AP diets (fasted and fed states: P-diet<0.01). At the fasted state, PP-diet increased gut microbiota (e.g. indoleacrylic acid) and plant (salicylic acid derivatives, trigonelline) metabolite levels. On the contrary, AP-diet increased methylhistidine (MH), betaine, hydroxyproline, methionine, lysine and α-aminoadipic acid levels. For some of these metabolites (e.g. α-aminoadipic acid or MH), the same associations were found at the fed state after the challenge meal, while the analysis of the postprandial metabolome interestingly revealed additional associations that were not visible at the fasting state (PP vs AP-diets: lower methionine sulfoxide level; higher deoxycholic acid, pyroglutamic acid and proline levels). While some of these metabolites seem to be food intake biomarkers (e.g. MH for meat intake) others have been associated with cardiometabolic risk (α-aminoadipic acid, increased with AP-diet, associated with higher risk of diabetes) and bring new mechanistic insights to unravel the subtle changes induced by plant-based diet on cardiometabolic risk.