Though Farnesiferol C (FC) derived from Ferula asafoetida is known to have antiangiogenic and apoptotic effect in gastric, breast, nonsmall lung cancers, the underlying antitumor mechanism of FC is not fully understood so far. Hence, in the current study, apoptotic mechanism of FC was explored in colon cancers in association with carbon catabolite repression 4-negative on TATA-less 2 (CNOT2)/c-Myc signaling. Herein FC significantly increased cytotoxicity and reduced the number of colonies in HCT116 cells more effectively than in SW480 cells, though FC enhanced sub-G1 cell population in HCT116 and SW480 cells compared to untreated control. Consistently, FC activated the cleavages of Poly ADP-ribose polymerase (PARP) and Bax and attenuated the expression of pro-PARP and Cyclin D1 in HCT116 cells better than SW480 cells. Also, FC significantly reduced the expression of CNOT2 and c-Myc. Also, FC reduced of c-Myc stability in HCT116 cells by cycloheximide assay. Notably, CNOT2 depletion reduced the expression of c-Myc, while c-Myc depletion also attenuated the expression of CNOT2 in HCT116 cells, implying the crosstalk between CNOT2 and c-Myc. Furthermore, overexpression of c-Myc or CNOT2 promoted the expression of pro-PARP in HCT116 cells. Overall, these findings suggest that FC induces apoptosis via inhibition of CNOT2 and c-Myc in colon cancers for a potent anticancer candidate for further agriculture cultivation in Korea.