The action of the play takes place during the final hours of Dr Vivian Bearing, a university professor of English, dying of ovarian cancer. She recalls the initial diagnosis of Stage IV metastatic ovarian cancer from her oncologist, Dr Harvey Kelekian. Dr Kelekian then proposes an experimental chemotherapeutic treatment regimen consisting of eight rounds at full dosage. Vivian agrees to the treatment.
Over the course of the play, Vivian reflects on her life through the intricacies of the English language, especially the use of wit in the metaphysical poetry of John Donne. Throughout the play, she recites Donne's Holy Sonnet X, "Death Be Not Proud," while reflecting upon her condition. (In the revised edition of John Donne's Holy Sonnets, "If Poysonous Mineralls" and "Death Be Not Proud" are sonnets IX and X, respectively.) As a professor, she has a reputation for rigorous teaching methods. She has lived her life alone, is unmarried and without children, her parents are deceased, and she has no emergency contact.
Vivian recalls undergoing tests by various medical technicians and being the subject of grand rounds. She remembers sharing a love of language and books with her father. She flashes back to her experiences as a student of Dr E. M. Ashford, an expert on John Donne. Bearing later finds herself under the care of Dr Jason Posner, an oncology research fellow who has taken her class on John Donne. At the hospital, she recognizes that doctors are interested in her for her research value and, like her, tend to ignore humanity in favor of knowledge. Gradually, she realizes that she would prefer kindness to intellectualism.
Vivian reaches the end stage in extreme pain as Susie Monahan, a nurse at the medical centre, offers Vivian compassion and discusses with her the option of exercising her final option, "do not resuscitate" (DNR), in case of a severe decline in her condition. Vivian decides to mark the DNR option. Dr Ashford, in town for her great-grandson's birthday, visits the hospital after learning of Vivian's cancer. She comforts her and offers to read a Donne sonnet, but Vivian, scarcely conscious, declines. Instead, Ashford reads from Margaret Wise Brown's The Runaway Bunny, which she had bought for her great-grandson. It is arguable that Dr Ashford was a figment of Vivian's imagination, as she disappears from the script without any exit.
When Vivian flatlines, Jason tries to resuscitate her, and calls in a medical team to administer CPR. Susie tries to stop him, pointing out the DNR instruction. Jason eventually realizes his mistake and calls for the CPR team to stop. The play ends as Vivian, unclothed after her death, walks from her hospital bed "toward a little light".