Myeloid cell leukemia 1 (MCL-1) is a member of the B-cell lymphoma 2 protein family and has anti-apoptotic functions. Deregulation of MCL-1 has been reported in several cancers, including lung and breast cancer. In the present study, the association of MCL-1 expression with molecular features in colorectal cancer (CRC) has been highlighted. CRC samples from Caris Life Sciences (Phoenix, AZ) were analyzed using NextGen DNA sequencing, whole transcriptome sequencing, whole exome sequencing, and immunohistochemistry (IHC); and stratified based on MCL-1 expression as top quartile MCL-1 (Q4) and bottom quartile MCL-1 (Q1). Immune cell infiltration (CI) in the tumor microenvironment (TME) was measured using RNA deconvolution analysis (QuanTIseq). MCL-1 tumors were associated with an increased rate of programmed death ligand 1 IHC, higher T cell-inflamed signature, interferon score, microsatellite instability-high and tumor mutational burden-high status. MCL-1 was associated with higher mutation rates of BCOR, TP53, KMT2D, ASXL1, KDM6A, ATM, MSH6, SPEN, KRAS, STK11, GNAS, RNF43, and lower mutation rates of CDKN1B, NRAS, and APC, and copy number amplifications in several genes. MCL-1 TME had higher CI of M1 and M2 macrophages, B cells, natural killer cells, neutrophils, and T-regulatory cells infiltration, and lower CI of myeloid dendritic cells. Higher MCL-1 expression is significantly associated with favorable clinical outcomes in CRC cohorts. Our data showed a strong correlation between MCL-1 and distinct immune biomarkers and TME CI in CRC. Our findings suggest MCL-1 is a potential modulator of antitumor immunity, TME, and biomarker in CRC.