Doomsday Book is the story of Kivrin Engle, a time traveling historian who travels back to the time of the Black Death. Simultaneously, a wave of influenza sweeps through near-future London and creates a parallel series of deaths and outbreaks. Kivrin and her mentor, Dunworthy, must struggle to make sense of their straits as they try to return to the future but find themselves caught between the two deadly plagues.
Kivrin Engle, a young historian specializing in medieval history, asks her reluctant instructor, Professor James Dunworthy, and the authorities running the project to send her to Oxford in 1320. This period had previously been thought too dangerous, because it stretched the time travel net 300 years earlier than it had ever been used before. Professor Gilchrist, who took charge of the project in the absence of the normal department head, coaxes authorities to allow it, in hopes it would enhance his own prestige. Kivrin will be the first historian to visit the period and is confident that she is well prepared for what she will encounter.
Shortly after sending Kivrin to the 14th century, Badri Chaudhuri, the technician who set the time travel coordinates for Kivrin's trip, collapses suddenly, an early victim of a deadly new influenza epidemic that then disrupts the university and eventually leads to the entire city's being quarantined. The time traveler Kivrin also falls ill as soon as she arrives in the past. She awakens, after several days of fever and delirium, at a nearby manor, whose residents have nursed her. Being moved by her rescuers caused her to lose track of where the "drop point" is (in order to return home, she must return to the exact location where she arrived, when the gateway opens at a prearranged time).
The narrative switches between Kivrin in the 14th century and 2054/2055 Oxford during the influenza epidemic. Kivrin discovers many inconsistencies in what she "knows" about the time: the Middle English she learned is different from the local dialect, her maps are useless, her clothing is too fine, and she is far too clean. She can also read and write, skills unusual even for educated men of the time and rare among women. As nuns are the only women commonly possessing these skills, some family members conclude Kivrin has fled her convent and plan to return her to the nearest convent. She fakes amnesia, afraid the background story she originally concocted would have similar inconsistencies, as she tries to find the "drop point".
In future Oxford, fears grow that the virus causing the epidemic has been transmitted from the past via the time travel net, despite the scientific impossibility of that occurrence. This causes Professor Gilchrist to order the net closed, effectively stranding Kivrin in the past, even as Professor Dunworthy tries frantically to reverse the decision.
At parallel points in their respective narratives, Kivrin and Professor Dunworthy realize that she has been sent to England at the wrong time as a result of the technician's illness: she has arrived during the Black Death pandemic in England in 1348, more than 20 years later than her intended arrival. The Black Death cuts a swathe through the Middle Ages just as the influenza overwhelms the medical staff of the 21st century. Many who could have helped Professor Dunworthy fall ill and die, including his good friend Doctor Mary Ahrens, who dies even as she tries to save the other influenza victims, and Professor Dunworthy himself is stricken by the disease.
Meanwhile, in the 14th century, two weeks after Kivrin's arrival, a monk infected with the plague comes to the village. Within days, many residents of the village fall ill. Kivrin tries to nurse the victims, but, lacking modern medicines, she can do little to ease their suffering. The arranged date for retrieval passes with neither side able to make it. At last, in desperation, Professor Dunworthy (despite being in feeble health) arranges for Badri to send him back in time to rescue Kivrin, as he feels responsible for sending his student, so he thinks, to her death.
In the Middle Ages, Kivrin can only watch while all the people she has come to know die from the Black Death. The last is Father Roche, the priest who found her when she was sick and brought her to the manor. Father Roche insisted on staying with his parishioners, despite Kivrin's attempts to arrange an escape, as he feels it his duty to care for them although it may mean his own death. As Roche lies dying in the chapel, he reveals that he was near the drop site when Kivrin came through and misinterpreted the circumstances of her arrival (shimmering light, condensation, a young woman appearing out of thin air) as God delivering a saint to help during the mysterious illness sweeping through England. He dies still believing that she is God's messenger to him and his congregation, while Kivrin comes to appreciate his selfless devotion to his work and to God.
As she sits in the graveyard, unable to dig a grave or finish tolling the peal for his death, her rescuers, Professor Dunworthy and Colin (the adventurous great-nephew of Doctor Mary Ahrens), find her. They barely recognize her: her hair is cropped short (from when she was sick with the flu), she is wearing a boy's jerkin, and she is covered in dirt and blood from tending to the sick and dying. The three return to 21st century England shortly after New Year's Day.