The story is set on the Princeton campus during the Easter weekend, 1999. The story involves four Princeton seniors, friends and roommates, getting ready for graduation: Tom, Paul, Charlie and Gil. Two of the students, Tom and Paul, are trying to solve the mystery contained within an extremely rare, beautifully decorated and very mysterious book— the Hypnerotomachia Poliphili. The Hypnerotomachia Poliphili published as an incunabulum in 1499 in Venice; it is a complex allegorical work written in a bizarrely modified Italian frequently interspersed with material from other languages as well as its anonymous author's own made-up words.
Tom, the narrator, is the son of a professor who had dedicated his life to theHypnerotomachia Poliphili. Throughout the novel, he struggles between being fascinated by the book and trying to pull away from the obsession that drew a rift between his father and his mother and is now causing discord between him and his girlfriend, Katie Marchand.
His roommate, Paul Harris, is a brilliant young scholar who is writing his undergraduate thesis on the Hypnerotomachia Poliphili. He has spent all four of his undergraduate years studying the book and is close to a breakthrough.
Charlie Freeman, the roommate who acts as the parent of the four friends and Gil, heir to a wealthy East Coast banking family are supporting characters to Tom and Paul's project.
The novel charts the relationship between the four roommates and how obsession can be both a boon and a burden. It is a story about growing up as much as solving the mystery of the Hypnerotomachia Poliphili. The disciplines of Renaissance science, history, architecture, and art are drawn upon to solve the mystery.
Tom, or Thomas Corelli Sullivan, often found himself distracted by his father's death. His father was a close friend of Richard Curry and Vincent Taft, both of them being advisors for Paul in his thesis. The flashback goes on as Taft distanced himself from both Curry and Tom's father at some point to carry out his own research. Taft also developed a rivalry with both men in the quest to decode theHypnerotomachia's 500-year-old secret. By luck, Tom's father found a letter, dating back to Renaissance times, referring to the book's supposed author, Francesco Colonna. Tom's father even wrote a book, The Belladona Document, which revolves around the mysterious letter. But, a negative critique from his academic rival Vincent Taft spelled the demise of the book's popularity as well as Tom's father's career. Taft allegedly also stole a diary written by a contemporary of Colonna's that Curry had found. That diary, as Paul and Tom discovered it later, would prove to help the duo to decode the elusive Hypnerotomachia.
In the end, Paul discovers that the Hypnerotomachia contains a number of hidden and enciphered texts, with the solution to each one revealing a clue towards the next one. However, after solving a chain of several of these, he finds a text that says that there will be no more clues and he must solve the rest of the book on his own. He realizes that the entire book contains a message encoded by following a "rule of four", in which the message starts with one letter, then moves to a letter four rows down, then ten columns right, then two rows up, then two columns left, and repeating. The placement of this hidden text throughout the entire book explains theHypnerotomachia's strange syntax, use of multiple languages, and neologisms. Through days of tough work, Paul and Tom managed to unravel a series of riddles, which they solved soon later. The application of the "rule of four" method enabled the duo to slowly piece together portions of a dark Renaissance secret that has avoided human knowledge for centuries.
The author of the Hypnerotomachia Poliphili, Francesco Colonna, was a humanist in Renaissance Florence. He was an ardent fan of knowledge, books, arts and anything that has a Renaissance identity on it. His passion for Greek and Roman literature was immense. But, one Girolamo Savonarola saw the exact opposite ; Florence is gradually turning into an free-thinking city, with its people starting to forget God and worshipping knowledge. As soon as he grasps power in Florence, Savonarola started the infamous Bonfire of the Vanities, a practice of burning books and art that seemed to contain elements of blasphemy. Colonna could not stand this practice and confronted Girolamo Savonarola himself as a sign of protest, only to be disappointed. Colonna started the building of a large underground vault to seal away a number of ancient books and pieces of art to preserve them from the followers of the priest. On one occasion, to prove his stand, Francesco and two of his men walked onto the raging inferno of the bonfire. As a result, Francesco met a fiery end. As he expected, the death of Francesco sparked cry against the reign of Savonarola, who was later hanged and burnt to ashes. Before dying, Colonna wrote the Hypnerotomachia, a book of codes on his efforts to uplift humanism despite religious dogmas. He disguises its contents in a seemingly innocent piece of Renaissance romantic literature, concerning the love between Poliphilo and Polia. Hypnerotomachia Poliphili itself meant "Poliphilo's Struggle of Love in a Dream".
It also turns out that Paul's friend Bill Stein and his thesis advisor Vincent Taft were conspiring together to steal Paul's thesis and claim credit for it, and the sealed vault of treasures. They were murdered by Paul's wealthy but unstable benefactor Richard Curry to prevent this from happening.
In a final struggle between a team of Tom, Gil and Paul against Richard Curry, a fire breaks out at Ivy Club, a Princeton eating club of which Gil is the president. After much persuasion by both Tom and Paul to save each other from the fire, Tom jumps out of a window to be rescued by the firemen. Paul does not manage to do so, leading both Tom and Gil to assume that he must have died in the fire together with Curry.
Five years pass. Charlie is already married with two children; Tom is still traumatised by the event that occurred that day. He has subsequently become a software analyst and gotten engaged to another woman, only for it to fail later. One day, he receives a tube in the mail containing an authentic ancient (and unknown) Botticelli canvas. The tube has a mysterious return address in Florence, Italy. Tom realises the address is a code by his long lost friend Paul Harris, urging him to head towards Italy soon. The story ends with Tom packing his clothes and reconnecting with Katie by phone, telling her that he is leaving for Italy and that he wants to see her when he returns
