Iron deficiency (ID) exhibits strikingly high prevalence in colorectal cancer (CRC), yet its prognostic implications remain insufficiently characterized. This study aimed to evaluate the association between pre-treatment ID status and therapeutic outcomes in patients undergoing standardized treatment protocols for CRC.A retrospective cohort of 1003 CRC patients was analyzed to assess the prevalence of ID and its correlations with clinicopathologic features, postoperative recovery, neoadjuvant therapy response, and iron metabolism and ferroptosis-related gene expression. The association of ID with clinicopathologic data, laboratory parameters, and treatment patient outcome was analyzed using logistic regression. Prussian blue staining was used to assess iron levels in tumor and adjacent noncancerous tissues. Bioinformatics was employed to analyze the expression levels of iron metabolism and ferroptosis-related genes.ID was identified in 50.85% (510/1003) of patients. Compared with non-ID patients, those with ID exhibited higher female predominance (56.8% vs. 43.2%), significant increased prevalence of anemia (76.2% vs. 23.8%), and elevated levels of C-reactive protein (CRP), along with decreased albumin (Alb) levels. Clinicopathologic associations with ID included larger tumor diameter, more advanced pathological T/N/M stages, poorer tumor differentiation, and increased lymphovascular and perineural invasion. Among patients received neoadjuvant therapy, ID was associated with higher clinical T/N stages and lower tumor regression grades. Postoperatively, ID patients experienced significantly longer time to first flatus, lower albumin levels, and elevated inflammatory markers. Prussian blue staining revealed reduced iron content in both tumor and adjacent tissues of ID patients. Molecular analyses identified dysregulated iron metabolism genes, with DMRT1, HAMP, FTH1, FTL, TFRC, LCN2, PCBP1 and PCBP2 upregulated and ACO1, IRPEB2, OTUD1, SLC40A1 and NCOA4 downregulated in tumor tissues. Ferroptosis suppressor genes (LCN2, TFRC and SLC40A1) were overexpressed in non-responders to chemoradiotherapy.ID is closely associated with aggressive tumor biology, suboptimal response to neoadjuvant therapy, and impaired postoperative recovery. Dysregulation of iron homeostasis and ferroptosis pathways in ID patients may contribute to CRC progression. These findings highlight ID as a potential biomarker for risk stratification and suggest that targeting iron metabolism could improve therapeutic outcomes in CRC management.© 2025. The Author(s).