Sitophilus zeamais is one of the most destructive pests of stored grains. Both adults and larvae penetrate and consume the grains, thereby diminishing the grain quality and nutritional value. We determined the chemical composition of Angelica archangelica essential oil, its fumigation toxicity against S. zeamais, and its effects on the activities of detoxification enzymes in the insects. RNA-seq was performed to analyze the impact of the essential oil on the transcriptional level of S. zeamais, and qRT-PCR was conducted to validate the differentially expressed genes. Chemical analysis identified 35 components in essential oil, including δ-3-Carene (24.26%), Limonene (19.81%), and α-Pinene (14.96%). A significant positive correlation was observed between the fumigation activity of the essential oil and the applied dose. The median lethal concentrations (LC50) values were 164.38, 132.62, and 90.35 mg/L air at 24, 48, and 72 h, respectively. Fumigation significantly inhibited the activities of the three detoxification enzymes. RNA-seq revealed a total of 3718 significantly differentially expressed genes (DEGs). qRT-PCR confirmed that the expression patterns of the DEGs were consistent with the RNA-seq data. This study comprehensively evaluates the control efficacy of A. archangelica essential oil against S. zeamais and provides data support for developing novel, eco-friendly, plant-based pesticides.