Death Masks is the story of Harry Dresden, a wizard detective living in Chicago, who is drawn into a case when a powerful demon, Nicodemus, steals the Shroud of Turin and uses it to cause a terrible plague. Harry, aided by three holy knights, races to stop Nicodemus and prevent the plague from touching off a Biblical apocalypse. Harry's journey is marred by loss and injury, but in the end he is able to thwart Nicodemus's designs.
Harry shares a TV panel with a Vatican priest, Father Vincent, and São Paulo University Professor Don Paolo Ortega, a disguised Red Court Vampire noble. Father Vincent hires Dresden to recover the stolen Shroud of Turin while Ortega challenges Harry to a duel to end the war between the White Council and the Red Court. After the show concludes, Dresden is attacked by the Denarian Ursiel, a fallen angel attached to a mortal host. Michael Carpenter and two other Knights of the Cross, Shiro and Sanya, rescue him and ask him to drop the Shroud investigation, but Dresden refuses.
Dresden tracks the Shroud to a boat, but is captured by the thieves. Deirdre, another Denarian, attacks the boat and kills one of the thieves. Dresden fools her into taking a decoy safe rather than the Shroud itself.The surviving thief, Anna Valmont, flees with the Shroud. Dresden's onetime lover, Susan Rodriguez, escorts him to a high society art sales charity event run by Johnny Marcone, where the Shroud will likely be sold. The sale is interrupted by the Denarians, who seize the Shroud and kidnap Dresden.
Nicodemus, leader of the Denarians, pressures Harry to join with the Denarian Lasciel or die. Dresden refuses. Shiro arrives and trades himself for Dresden. Dresden is almost re-captured, but Susan, enhanced in battle by her semi-vampire status, helps him escape. She reveals that she is working with The Fellowship of St. Giles, an organization of half-turned humans resisting the vampire Courts. Harry deduces that Father Vincent is an Denarian imposter, and the real priest is the murder victim he is investigating for Murphy. With the Knights, he captures the imposter and forces him to reveal that Nicodemus plans to use the Shroud to create a deadly plague curse at O'Hare Airport, an international travel hub.
Dresden fights his duel with Ortega at Wrigley Field, overseen by The Archive (a little girl containing the sum of humanity's written knowledge) and her bodyguard Kincaid. Ortega, facing defeat, draws a forbidden weapon. He is shot by Martin, one of Susan's associates. Red Court vampires surge onto the field, covering Ortega's escape. Dresden races to the airport with the Knights. They find Shiro severely tortured and near death. Shiro entrusts his sacred sword Fidelacchius to Dresden and reveals that Nicodemus is now going to St. Louis by train to spread the plague curse. He then dies. Dresden enlists the aid of Marcone and catches up to the St. Louis train. Dresden, Marcone, and the Knights battle the Denarians to retrieve the Shroud. They recover the Shroud and stop the plague, but Nicodemus escapes and Marcone appropriates the shroud.
While Dresden recuperates in Michael's home, he receives a letter from Shiro, who reveals he is dying of cancer and intended to sacrifice himself. Dresden's White Council mentor, Ebenezar McCoy, wipes out Ortega's Latin American compound by crashing a satellite into it. Dresden trails Marcone to a secluded, rural hospital and discovers that Marcone is using the Shroud in an attempt to heal the comatose Amanda Beckitt. Dresden tells Marcone he can have three days to see if the Shroud will heal her, then return it to the Church. Marcone agrees. Nicodemus attempts to suborn Michael's youngest son into the Denarian order, but Dresden thwarts him, but not without pain and cost.