Gut microbiota (GM) has emerged as an essential and integral factor for maintaining human health and affecting pathological outcomes. Metagenomics and metabolomics characterization have furthered gut metagenome’s understanding and unveiled that deviation of specific GM community members and GM-dependent metabolites imbalance orchestrate metabolic or cardiovascular diseases (CVDs). Restoring GM ecosystem with nutraceutical supplements keenly prebiotics and probiotics relatively decreases CVDs incidence and overall mortality. In Atherosclerosis, commensal and pathogenic gut microbes correlate with atherogenesis events. GM-dependent metabolites-trimethylamine N-oxide and short-chain fatty acids regulate atherosclerosis-related metabolic processes in opposite patterns to affect atherosclerosis outcomes. Therefore, GM might be a potential therapeutic target for atherosclerosis. In atherogenic animal models, natural products with cardioprotective properties could modulate the GM ecosystem by revitalizing healthier GM phylotypes and abrogating proatherogenic metabolites, paving future research paths for clinical therapeutics.