An architect works to build up the 1893 World's Fair, while the serial killer H. H. Holmes uses the fair to attract and kill women.

The book is set in Chicago in 1893, interweaving the true tales of Daniel Burnham, the architect behind the 1893 World's Fair, and H. H. Holmes, a serial killer who lured his victims to their deaths in his elaborately constructed "Murder Castle". The Devil in the White City is divided into four parts, the first three happening in Chicago between 1890 and 1893, while part four of the book takes place in Philadelphia circa 1895. The story of Daniel Burnham, his building of the fair, and the struggles he overcomes forms one plot line. The other, a vivid and very different plot line, is that of H. H. Holmes, a mentally unstable pharmacist/doctor who forms a plan to use an abandoned lot across the street from his pharmacy to lure and kill multiple victims.