UNLABELLED: The widespread environmental presence of triclosan (TC), a common antimicrobial agent, has raised concerns about its potential metabolic and neurological effects, particularly in susceptible populations such as individuals with diabetes. This study investigated the neuronal effects of TC in streptozotocin (STZ)-induced diabetic zebrafish larvae using network pharmacology, toxicity assays, and gene expression analysis. Network pharmacology identified 99 overlapping diabetes-related targets, with KEGG analysis implicating AGE-RAGE signaling and cholinergic synapse pathways in diabetic and neuronal complications. Acute toxicity testing revealed that TC and STZ co-exposure caused developmental abnormalities, including pericardial edema, and reduced survival (48%) compared to TC (76%) or STZ (68%) alone. Oxidative stress assays demonstrated synergistic reactive oxygen species elevation in the TC + STZ group, supported by upregulated antioxidant enzymes and glutathione-related genes. Neuronal toxicity assessments showed reduced acetylcholinesterase (AChE) activity and impaired locomotor behavior in diabetic larvae exposed to TC, indicating disrupted cholinergic signaling and cognitive dysfunction. Behavioral analyses confirmed hypoactivity and erratic swimming patterns, aligning with oxidative stress and neuroinflammation. These findings suggest that TC exacerbates diabetes-associated hyperglycemia, oxidative stress, and neurotoxicity, with synergistic effects under diabetic conditions. The study highlights the need for diabetes-specific therapeutic strategies, such as antioxidant and neuroprotective interventions, and stricter safety guidelines for TC use in diabetic populations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04352-z.