The antimitotic anti‐cancer drugs, including taxol, perturb spindle dynamics, and induce prolonged, spindle checkpoint‐dependent mitotic arrest in cancer cells. These cells then either undergo apoptosis triggered by the intrinsic mitochondrial pathway or exit mitosis without proper cell division in an adaptation pathway. Using a genome‐wide small interfering RNA (siRNA) screen in taxol‐treated HeLa cells, we systematically identify components of the mitotic apoptosis and adaptation pathways. We show that the Mad2 inhibitor p31comet actively promotes mitotic adaptation through cyclin B1 degradation and has a minor separate function in suppressing apoptosis. Conversely, the pro‐apoptotic Bcl2 family member, Noxa, is a critical initiator of mitotic cell death. Unexpectedly, the upstream components of the mitochondrial apoptosis pathway and the mitochondrial fission protein Drp1 contribute to mitotic adaption. Our results reveal crosstalk between the apoptosis and adaptation pathways during mitotic arrest. Synopsis Prolonged mitotic arrest induced by anti‐proliferative drugs eventually results in apoptotic cell death or in mitotic exit due to checkpoint adaptation. An RNAi screen in human cancer cells lines offers new insights into the regulatory networks underlying these processes. Genome‐wide siRNA screen identifies regulators of mitotic cell death and checkpoint adaptation. The BH3‐only protein Noxa promotes apoptosis during mitotic arrest. The spindle checkpoint regulator p31comet suppresses mitotic adaptation and facilitates apoptosis. A Bax/Bak mitochondrial module couples mitotic apoptosis and adaptation. The mitochondrial fission factor Drp1 promotes mitotic checkpoint adaptation. An RNAi screen offers new insights into the regulatory networks governing the fate of cancer cells undergoing prolonged drug‐induced mitotic checkpoint arrest.