Abstract <p>This paper describes a simple, sensitive, and specific headspace gas chromatography method that has been developed and validated for the quantitation of acryloyl chloride, a potential mutagenic impurity in a drug substance. Using ethanol as the derivatizing agent, acryloyl chloride is converted to ethyl acrylate, which is quantitated with headspace gas chromatography. Quantitation was performed with an external standard by thermostating the sample and standard before analysis, allowing for high extraction of the analyte in the gas phase of the headspace vial. The method is sensitive, with a limit of quantitation (<b>LOQ</b>) of 10 ppm for acryloyl chloride in the drug substance. This method, combined with its high sensitivity and the incorporation of headspace sampling, represents the first of its kind for quantifying acryloyl chloride at low levels in a pharmaceutical matrix. The performance of the method was evaluated by assessing parameters like specificity, linearity, precision, LOQ, and solution stability. The developed method was successfully used to quantify acryloyl chloride accurately in samples of the drug substance. The specificity, sensitivity, and simplicity of this method make it suitable for the quantitation of acryloyl in the drug substance at trace levels. This method is applicable to other drug substance matrices with minimal method adjustments.</p>