SPP1+ macrophages have been identified as key players in the colorectal cancer (CRC) tumor microenvironment, but their function remains unclear. This study integrated single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of SPP1+ macrophages in CRC. Our findings revealed a pronounced elevation of SPP1+ macrophages in CRC, especially within tumor territories. These macrophages served as markers for CRC initiation, progression, metastasis, and potential prognosis. Furthermore, they showed heightened transcriptional activity in genes linked to angiogenesis, epithelial–mesenchymal transition, glycolysis, hypoxia, and immunosuppression. SPP1 protein amplified CRC cell migration and invasion, potentially mediating cellular crosstalk via the SPP1-CD44, SPP1-PTGER4, and SPP1-a4b1 complex axes. Patients with a high proportion of SPP1+ macrophages could benefit more from immune checkpoint blockade therapy. Interestingly, CSF1R expression was significantly enriched in C1QC+ macrophages versus SPP1+ macrophages, possibly explaining limited anti-CSF1R monotherapy effects. In conclusion, we propose an SPP1+ macrophage model in CRC, highlighting such macrophages as a promising therapeutic target due to their malignancy markers.