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Non-communicable diseases (NCDs), including type 2 diabetes mellitus (DM), hypertension (HTA), obesity (OB), and cardiovascular disease (CVD), represent a major global health burden and disproportionately affect socially vulnerable populations. Small extracellular vesicles (EVs) are stable carriers of proteins and regulatory RNAs that may reflect endothelial dysfunction and cardiometabolic stress. This study explored plasma-derived EV-associated biomarkers in adults from La Guajira, Colombia, with emphasis on miR-126-3p, miR-21-5p, miR-92a-3p, and SNAIL. Anthropometric, clinical, and biochemical data were obtained from a cross-sectional cohort. Representative plasma samples were selected for EVs isolation by size-exclusion chromatography. Vesicles were characterized by nanoparticle tracking analysis, scanning transmission electron microscopy, protein quantification, Western blotting, and bead-based flow cytometry. Candidate miRNAs were identified by small RNA sequencing and validated by stem-loop RT-qPCR. Bioinformatic enrichment analyses were performed using miRNet 2.0 and KEGG pathway analysis. The epidemiological cohort showed a high cardiometabolic burden, with waist-to-height ratio (WHtR) and triglyceride-glucose (TyG) index emerging as key markers of central adiposity and metabolic dysfunction. Plasma-derived EVs displayed the expected nanoscale morphology and expressed canonical vesicle markers. Protein cargo analyses revealed EMT- and remodeling-associated proteins, including SNAIL and GAL-3. EV-associated miR-126-3p, miR-21-5p, and miR-92a-3p were enriched predominantly in hypertensive and hypertensive-diabetic groups. In an exploratory sub-cohort, CD31-positive EVs showed a trend toward increased expression in individuals with previous myocardial infarction or stroke (p = 0.057). KEGG enrichment analysis linked the identified miRNA signature to pathways involved in endothelial dysfunction, inflammation, vascular remodeling, apoptosis, and extracellular matrix organization. Plasma-derived EVs from individuals with cardiometabolic disorders carry molecular signatures consistent with endothelial stress and vascular remodeling. These findings identify miR-126-3p, miR-21-5p, miR-92a-3p, SNAIL, and CD31-positive EVs as exploratory candidate biomarkers that require validation in larger prospective cohorts.