Background <p>Inflammatory dysregulation and synaptic dysfunction have been implicated in the pathophysiology of agitation in schizophrenia (SZ), but the underlying molecular mechanisms remain unclear. Plasma exosomal microRNAs (miRNAs) are stable circulating molecules that may reflect disease-related molecular alterations associated with schizophrenia. This study aimed to investigate plasma exosomal miRNA expression profiles and peripheral inflammatory factors in schizophrenia patients with agitation, and to identify potential biomarkers for agitation symptoms.</p> Methods <p>In this study, plasma exosomal miRNA expression profiles and peripheral inflammatory factors were compared between schizophrenia patients with agitation assessed within 24&#xa0;h of hospital admission using PANSS-EC (SZA group, <i>n</i> = 35) and those without agitation (SZN group, <i>n</i> = 29). Differentially expressed plasma exosomal miRNAs were identified and subjected to GO and KEGG enrichment analyses. Peripheral inflammatory factors, including cytokine levels, neutrophil counts, and neutrophil-to-albumin ratio (NAR), were also measured. Partial correlation analyses (adjusting for age, sex, BMI, chlorpromazine equivalent, and diazepam equivalent) with Bonferroni correction were performed. A binary logistic regression (LR) model with forward stepwise selection (fixed covariates: age, sex, BMI, chlorpromazine equivalent, and diazepam equivalent) was constructed to identify discriminating factors, followed by receiver operating characteristic (ROC) curve analysis and five‑fold cross‑validation.</p> Results <p>A total of 18 differentially expressed plasma exosomal miRNAs (15 upregulated, 3 downregulated) were identified in the SZA group. Target genes of upregulated miRNAs were enriched in MAPK and Ras signaling pathways, as well as cholinergic synapse and efferocytosis. Conversely, target genes of the downregulated miRNAs were specifically enriched in glutamatergic synapse. NAR showed a trend toward elevation in the SZA group (uncorrected <i>p</i> = 0.004, Bonferroni‑adjusted <i>p</i> = 0.088), while no significant differences in cytokine levels were observed. Partial correlation analysis revealed that in the SZA group, IL‑12p70 was positively correlated with miR‑3620‑5p (<i>r</i> = 0.893, adjusted <i>p</i> &lt; 0.001) and miR‑17‑3p (<i>r</i> = 0.768, adjusted <i>p</i> = 0.028). Multivariable logistic regression (including fixed covariates: age, sex, BMI, chlorpromazine equivalent, diazepam equivalent) retained NAR (OR = 3.778, <i>p</i> = 0.006) and miR‑543 (OR = 0.162, <i>p</i> = 0.026). The combined model (NAR + miR‑543 + fixed covariates) achieved an AUC of 0.812, outperforming single‑marker models (NAR AUC = 0.752, miR‑543 AUC = 0.715). Five‑fold cross‑validation yielded a mean AUC of 0.795 (95% CI 0.675–0.916), with sensitivity 80.1 ± 16.5%, specificity 79.5 ± 26.1%, and accuracy 77.8 ± 8.9%.</p> Conclusion <p>The findings suggest that schizophrenia patients with agitation exhibit distinct plasma exosomal miRNA expression profiles and peripheral inflammatory alterations compared to those without agitation. These findings also imply potential involvement of inflammation-associated signaling and synaptic pathways in the biological mechanisms underlying agitation in schizophrenia. Furthermore, the combination of NAR and miR-543 may serve as a potential biomarker for agitation assessment in schizophrenia, offering new insights into the biological mechanisms underlying this clinically challenging symptom.</p>