Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, creating an urgent need to identify new therapeutic targets. Semaphorin 7A (SEMA7A), a glycosylphosphatidylinositol (GPI)-anchored protein, has been implicated in tumor progression, but its role in CRC, tumor microenvironment (TME), and inflammation-related CRC remains unreported. In this study, we first confirmed that SEMA7A is highly expressed in CRC tissues, linked to lymphatic metastasis and advanced tumor node metastases (TNM) stage by bioinformatics and clinical cohort analysis. Furthermore, by silencing SEMA7A in CRC cell lines, there was a significant inhibition of tumor growth, endothelial cell migration, and angiogenesis. In the TME, culture medium derived from SEMA7A-knockdown CRC cells inhibited the infiltration of tumor-associated macrophage (TAM) and their polarization toward a pro-tumor M2 phenotype. Moreover, our study revealed that in the colitis-associated CRC model induced by azoxymethane/dextran sodium sulfate, down-regulation of SEMA7A significantly reduced the tumor burden, with marked suppression of macrophage recruitment, expression of M2-like TAM markers, and angiogenesis. Subsequently, we focused on PlexinC1, the high-affinity receptor for SEMA7A, through transcriptomic analysis and demonstrated that SEMA7A activates the RAP1/AKT signaling pathway through PlexinC1 receptor in TAM. The rescue experiments using recombinant SEMA7A (rhSEMA7A) further indicated that blocking PlexinC1 suppressed the conversion of macrophages into M2-like TAM in the CRC microenvironment. Collectively, our findings demonstrated that SEMA7A can act as a key regulator of CRC progression, coordinating tumor-intrinsic and TME processes, and highlight its potential as a therapeutic target.