Colorectal cancer (CRC) is a leading cause of cancer death, with resistance and apoptosis evasion—often via Bcl-2—representing major challenges. The redox-modulating drug dimethyl fumarate (DMF) has demonstrated efficacy in hematologic malignancies; however, its potential in solid tumors remains unclear. Here, we show that DMF, especially in combination with the Bcl-2 inhibitor venetoclax (ABT-199), induces apoptosis in HCT-116 CRC cells. DMF impairs mitochondrial respiration, causing membrane hyperpolarization, ATP depletion, autophagy, and cell cycle arrest. Combined treatment increases metabolic stress, reduces proliferation, and induces sustained G2 arrest with downregulation of cyclins and CDKs. These findings highlight a combined effect targeting redox balance and apoptosis in CRC. Given their clinical availability, DMF and ABT-199 represent a promising combination for further preclinical evaluation.