Understanding the role of the tumor microenvironment in colorectal cancer (CRC) progression remains a challenge due to its complexity. Investigating the interplay between immune cell characteristics, serum metabolites, inflammatory protein factors, and CRC could unveil novel therapeutic avenues. We used 2-sample Mendelian randomization (MR) on Genome-Wide Association Studies (GWAS) data to explore causal links between 731 immune cell characteristics, 1400 serum metabolites, 91 inflammatory proteins, and CRC. Various MR methods, including inverse variance weighted (IVW) and MR-Egger, were applied to ensure robust analysis. Sensitivity analyses, such as the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis, were performed to check for pleiotropy, heterogeneity, and influential outliers. Following rigorous genetic variation screening, we identified 43 immune cell characteristics associated with CRC. Notably, 7 immunophenotypes, including CD39⁺ CD4⁺ T cell Absolute Count, exhibited significant associations as protective factors. Additionally, 36 other immunophenotypes showed significant causal relationships with CRC. Among serum metabolites, 37 were correlated with CRC, with 1-arachidonoyl-gpc (20: 4n6) being the most closely linked as a risk factor. Similarly, 36 serum metabolites displayed significant causal relationships with CRC. Seven inflammatory protein factors exhibited causal relationships with CRC, with 4 posing as risk factors and 3 as protective factors. Our study scrutinized 731 immune cell characteristics, 1400 serum metabolites, and 91 inflammatory protein factors within the tumor microenvironment. We confirmed causal relationships between 43 immune cell characteristics, 37 serum metabolites, and 7 inflammatory protein factors with CRC. These findings offer novel insights into the potential etiology, prevention, and treatment strategies for CRC.