A dietary shift from plant protein (PP) sources to animal protein (AP) sources is encouraged both for environmental and health reasons, especially for limiting cardiometabolic risk (CMR). We aimed at characterizing the metabolic reorientations induced by a reasonable dietary shift from AP to PP sources in middle-age men at CMR. We conducted a 1-month cross-over randomized controlled trial (NCT04236518) enrolling 19 healthy men with overweight and CMR. They randomly consumed 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 postprandially (6h followup) at the end of each intervention period after the intake of a high-fat challenge meal (900kcal, lipids=80%E). Multivariate (LiMM-PCA) and univariate mixed model analyses were performed. Plasma metabolome significantly differed between PP and AP diets at both fasted and fed states (Pdiet<0.01). At the fasted state, gut microbiota-related metabolites (e.g. indoleacrylic acid) and plant-derived metabolites (polyphenols degradation products, trigonelline, N-acetyl-ornithine) were higher after PP vs APdiets. Concomitantly, metabolites related to amino acid metabolism (lysine and its byproduct α-aminoadipic acid, branched chain amino acid (BCAA) catabolism products), gut microbiota-related metabolites (indoxyl sulfate) and meat or fish related food intake biomarkers (FIB) (methyhistidine, hydroxyprolines, EPA) were lower with PP vs AP-diets. The analysis of the postprandial metabolome revealed additional associations not visible at the fasting state, especially regarding lipid metabolism, with following PP vs AP-diets: lower levels of C3-acylcarnitine (related to BCAA catabolism) and higher postprandial increase of lipid species synthesized through the ω-oxidation (dicarboxylic acids C10, C12, C14, C16), a minor microsomal metabolic pathway. While some of these metabolites are validated FIB (e.g. methylhistidine for meat intake) others might be promising new ones, such as N-acetyl-ornithine, recently associated to PP intake. Some of the metabolic pathways or metabolites reported here have also been associated to increased CMR (BCAA degradation and α-aminoadipic acid) or decreased CMR (indoles produced by the gut microbiota tryptophan catabolism) and their levels are compatible with improved metabolic health after PP vs AP-diets. Additionally, the postprandial response to a high-fat challenge meal revealed unexpected changes in lipid metabolism, suggesting the activation of specific compensatory mechanisms in case of lipid overload and β-oxidation saturation following PP vs AP-diets. Overall, these results bring new mechanistic insights to unravel the subtle changes induced by plant-rich diets on CMR.