In plants, serpins form a superfamily of serine and cysteine protease inhibitors involved in stress tolerance and defense, with promising applications in pest management and agricultural biotechnology. This study identified and characterized 18 serpin (SiSRP) genes in the foxtail millet (Setaria italica) genome, distributed across different chromosomes. Analyses of gene structure, conserved motifs, and phylogeny indicated duplication events under strong purifying selection, driving the expansion and functional diversity of the serpin family. Prediction of cis-elements within promoter of SiSRP genes intimated that these serpin proteins are likely involved in plant's adaptive responses to abiotic stresses. Synteny with sorghum, rice, maize, and barley suggested that these genes originated before the divergence of these species, showing a close relationship between SiSRPs and sorghum genes. Expression profiles from RNA-seq data revealed functional diversification of these genes in plant development and defense. Multiple sequence alignment highlighted the LR gene (SiSRP9-2) as a promising candidate for pest control, disease resistance, and regulation of programmed cell death. This work provides the first genome-wide analysis of serpin genes in foxtail millet, offering valuable insights for enhancing crop stress tolerance. However, experimental validation of identified stress-related genes is required for dissecting the functional roles of serpins in crops like foxtail millet.