This study aimed to investigate the expression, prognostic significance, methylation, and immune invasion levels of secreted frizzled-related proteins (SFRP1-5) in colorectal cancer (CRC). Additionally, the relationship between SFRP1/2 methylation and immune infiltration in CRC was explored. The expression of SFRP1-5 was analyzed using several databases, including GEO, TCGA, TIMER, STRING, and GEPIA. Molecular interactions with SFRPs were examined via Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, and Genomes (KEGG) pathway analyses were conducted using the DAVID database. Methylation levels of SFRP1/2 in CRC were assessed through methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) experiments. Apoptosis and proliferation in CRC cells following the knockdown of SFRP1/2 expression were evaluated using flow cytometry and CCK-8 assays. The TISIDB database was used to analyze the relationship between SFRP1/2 methylation levels and immune infiltration. The expression of SFRP1, SFRP2, and SFRP5 was significantly lower in CRC patients, while SFRP4 expression was higher compared to that in healthy individuals. Elevated mRNA expression of SFRP2 was significantly associated with improved overall survival (OS), disease-specific survival, and progression-free intervals. SFRP1/2 expression was also linked to immune invasion, with higher levels correlating with increased immune infiltration. Both SFRP1 and SFRP2 showed hypermethylation in CRC. Knockdown of SFRP1/2 expression resulted in increased proliferation of CRC cells, and their methylation levels were inversely correlated with immune cell presence. The expression, methylation, and immune cell infiltration patterns of the SFRP family in CRC differed markedly from those in healthy individuals. These findings suggest that SFRPs may serve as potential therapeutic targets and key genes associated with immune cell infiltration in CRC.