Colorectal cancer (CRC) is the third most commonly diagnosed cancer and second leading cause of cancer-related deaths worldwide. This study explores the synergistic combination of doxorubicin and γ-tocotrienol on CRC cells, specifically Caco-2 and SW48, aiming to enhance doxorubicin’s efficacy while addressing its limitations of high-dose toxicity and resistance. Firstly, the in vitro antiproliferative effects were evaluated, followed by cellular and molecular assessments including histochemical and fluorescence staining, transmission electron microscopy (TEM), flow cytometry, and protein array analysis to elucidate the mode of cell death and protein expression changes. Combining sub-effective concentration of doxorubicin with γ-tocotrienol exhibited a chemosensitising effect, denoted by high synergy scores indicative of synergism. The combination treatment inhibited clonogenicity significantly, with a notable selectivity against cancer cells, as evidenced by negligible inhibition in normal colon (FHC) cells. Significant apoptotic cell death was observed, confirmed by annexin V staining and morphological changes. Besides, fluorescence staining and TEM revealed the formation of acidic vesicular organelles and autophagic vacuoles, signifying autophagy induction. This underscores the critical interplay between apoptosis and autophagy in this enhanced cell death. Furthermore, mitochondrial membrane depolarisation was observed. The use of inhibitor (cyclosporine A) altered cell death, indicating that mitochondria play a crucial role due to its regulatory role in the apoptotic and autophagic pathways. Molecularly, the downregulation of inhibitor of apoptosis family members (livin, survivin and XIAP) was observed, further highlighting the chemosensitising effect of γ-tocotrienol. Conclusively, combining doxorubicin and γ-tocotrienol enhanced chemosensitivity and reduced the required dosage via the co-induction of apoptosis and autophagy. Further investigations into the apoptotic and autophagic markers with the addition of respective inhibitors is warranted to confirm the underlying mechanisms driving this enhanced cell death.