Antipsychotics are the drugs most often involved in drug poisoning cases, and therefore, therapeutic drug monitoring (TDM) for is necessary safe and effective medication administration of these drugs.In this study, a coffee ring effect-based surface-enhanced Raman spectroscopy (CRE-SERS) method was developed and successfully used to monitor antipsychotic poisoning by using urine samples for the first time. The established method exhibited excellent SERS performance since more hot spots were obtained in the “coffee ring”. Using the optimized CRE-SERS method, the sensitivity was improved one order more than that of the conventional method with reasonable reproducibility. The antipsychotic drug clozapine (CLO) spiked into urine samples at 0.5-50 μg·mL-1 was quantitatively detected, at concentrations above the thresholds for toxicity. The CRE-SERS method allowed CLO and its metabolites to be ultimately distinguished from real poisoning urine samples. The coffee-ring effect would provide more opportunities for practical applications of the SERS-based method. The frequent occurrence of drug poisoning may have created a new area for the application of the CRE-SERS method. It is anticipated that the developed method will also have great potential for other drug poisoning monitoring.