Ethylene oxide (EO) and 2-chloroethanol (2-CE) are hazardous pesticide residues that pose significant risks to human health. EO is a carcinogenic compound linked to cancer, genetic mutations, and neurotoxicity, while 2-CE, a degradation product of EO, exhibits toxicity and may damage internal organs such as the liver and kidneys. These compounds are commonly used as fumigants in the food industry to eliminate microbes; however, their residues can persist in products, particularly in complex matrices like spice blends. Analyzing EO and 2-CE residues in such matrices is highly challenging due to matrix interference and sample preparation difficulties.   This study successfully developed and validated a method for analyzing EO and 2-CE residues in solid spice-based seasonings using GC-MS/MS with Headspace technology, without requiring matrix-matched standards. The method demonstrated excellent performance, with limits of detection (LODs) of 0.000095 mg/kg for EO and 0.0040 mg/kg for 2-CE, and limits of quantification (LOQs) of 0.00019 mg/kg for EO and 0.0060 mg/kg for 2-CE. Linearity was highly robust, with correlation coefficients (r) of 0.9999 for EO and 0.9998 for 2-CE. Recovery rates ranged from (81.19–95.35)% for EO and (80.75–87.31)% for 2-CE, complying with international validation guidelines such as SANTE/11312/2021.   This method eliminates matrix-matched standards while maintaining high accuracy, offering a cost-effective solution for EO and 2-CE analysis in complex spice matrices, with significant implications for global food safety regulations.