Background While left-sided colon cancer (LCC) is distinct from right-sided disease, its internal heterogeneity is poorly understood. This study compares prognosis and molecular features between sigmoid colon cancer (SigCC) and splenic flexure/descending colon cancer (SFDCC). Methods We analyzed epidemiological and survival data from the SEER database (35,858 patients) and multi-omics data from TCGA (350 patients). Propensity score matching balanced baseline characteristics. Survival analysis, Cox regression, functional enrichment (GO/KEGG/GSEA), and immune deconvolution (CIBERSORT) were performed. Results SigCC demonstrated significantly better overall survival (OS) and cancer-specific survival (CSS) than SFDCC before and after matching (P < 0.001). Multivariable analysis confirmed SigCC as an independent prognostic factor for improved OS (HR = 0.89) and CSS (HR = 0.91). Transcriptomic analysis revealed SigCC-related genes were enriched in apoptosis regulation and immune activation, while SFDCC-related genes were linked to extracellular matrix (ECM) remodeling and angiogenesis. The tumor immune microenvironment of SigCC exhibited higher regulatory T-cell and M2 macrophage infiltration, whereas SFDCC showed greater CD8 + T-cell presence. Conclusion SigCC is associated with a more favorable prognosis than SFDCC, potentially driven by distinct apoptotic and immune activation pathways versus pro-invasive ECM remodeling in SFDCC. These findings highlight significant heterogeneity within LCC, providing a basis for subtype-specific precision oncology.