To identify ferroptosis markers, which were associated with prognosis and immune response in colorectal cancer (CRC), we integrated spatial transcriptome, single-cell transcriptome, and bulk transcriptome data for analysis, and this multi-omics integration approach is an innovation that distinguishes this study from previous ones. We assessed the prognostic value of ferroptosis-related genes by Kaplan-Meier survival analysis, subject operating characteristic (ROC) curves, and Lasso analysis. A total of 135 ferroptosis-associated genes were identified, with the high-risk subgroup having significantly worse overall survival. The prognostic model showed strong predictive power. Immunohistochemistry (IHC) assay showed that Sorting Nexin 5 (SNX5) and Ubiquitin-specific protease 7 (USP7) were significantly up-regulated in CRC tissues compared with adjacent CRC tissues. Immune infiltration analysis revealed higher infiltration levels of CD8 + T cells, regulatory T cells, and resting NK cells in the high-risk group, as well as higher dysfunction scores, suggesting possible immunotherapy tolerance. Functional enrichment analysis revealed that the highly expressed genes were mainly enriched in extracellular matrix, integrin binding, and cell adhesion-related pathways. This study provides a comprehensive multi-omics framework for identifying prognostically relevant ferroptosis gene markers and immune response predictors in CRC, providing an important research foundation for precision oncology.