Book of Souls picks up the action a year after the conclusion of the international sensation Library of the Dead. Will Piper's life has been forever changed by the astonishing secret he discovered hidden at the government's clandestine installation deep under the Nevada desert. His uneasy retirement from the FBI is interrupted when a long-missing book surfaces at an auction house in London. A group of ex-Area 51 employees recruits Will to assist them in obtaining the book and in helping them solve a mystery that will affect the fate of all mankind. As government operatives try to stop him, Will discovers the ancient missing volume has had a profound effect on history. Remarkably, a newly found puzzle sonnet by a young William Shakespeare seems to have been inspired by the book.
As Will peels back the onion to solve a series of clues hidden in the poem, he finds the book has influenced not only Shakespeare but also the religious philosophy of John Calvin, the father of predestination, and the prophesies of the seer Nostradamus. When the final clue yields the ultimate secret, Will is forced to confront a truth which humanity may not be prepared to accept.