Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Identifying drug targets associated with CRC is crucial for developing targeted therapies. MR (IVW, Wald ratio, weighted median, and MR-Egger) and SMR analyses were used to screen candidate genes associated with CRC risk. Further validation was performed using The Cancer Genome Atlas (TCGA) to assess gene expression patterns and prognostic significance. Additionally, immune infiltration analysis was conducted to characterize the tumor immune microenvironment. Drug prediction was performed to explore potential therapeutic interventions. Eight genes were identified associated with CRC. , , , , , and were linked to an increased risk of CRC, whereas and were associated with a decreased risk of CRC. Notably, DBI exhibited a potentially favorable immune profile, negatively correlated with Tregs and MDSCs while positively associated with activated CD8 and CD4 T cells. Eight genes were identified as associated with CRC, among which exhibited a potential protective role, correlating with improved patient survival, enhanced immune activation, and increased responsiveness to immunotherapy. The remaining proteins demonstrated diverse and complex functions within the tumor immune microenvironment, providing novel insights for the development of precision diagnostics and immunotherapeutic strategies.