Abstract The study investigated the molecular basis of resveratrol (RSV)‐evoked apoptosis in four (Bax+/−, Bax−/−, p53+/+, and p53−/−) HCT116 colon cancer cell lines. RSV induced apoptosis in all the cells in a dose‐dependent manner; however, Bax+/− and p53+/+ cells were more susceptible than their knockout counterparts (Bax−/− and p53−/−, respectively). Using Bax+/− cells as a model, proteomic analysis revealed four RSV‐responsive events: fragmentation of lamin A/C protein; increase in concentration of a more basic isoelectric variant of the ribosomal protein P0; and decrease in concentration of dUTPase as well as stathmin 1. Lamin A cleavage in response to RSV treatment was confirmed using Western blot analysis. Caspase‐6 was activated, which was evidenced by cleavage and accumulation in active form of caspase‐6 as well as upregulation of the protease activity. RSV‐elicited lamin A cleavage and apoptosis were entirely abrogated by the peptide inhibitors of caspase‐6. Likewise, partial knockdown of caspase‐6 expression using small interfering RNA resulted in significant inhibition of RSV‐elicited lamin A cleavage and apoptosis. Furthermore, the lower apoptosis sensitivity of the knockout cells (Bax−/− and p53−/−) correlated with the relatively reduced processing of caspase‐6 and lamin A cleavage. Taken together, these data highlight the critical role of caspase‐6 and its cleavage of lamin A in apoptotic signaling triggered by RSV in the colon carcinoma cells, which can be activated in the absence of Bax or p53.