A graduate of the Cambridge School of Weston in Weston, Massachusetts, and Pomona College in Claremont, California, Preston began his writing career at the American Museum of Natural History in New York. In addition to his collaborations with Child, he has written several novels and non-fiction books of his own, mainly dealing with the history of the American Southwest. He is a contributing writer for Smithsonian, The Atlantic Monthly, and The New Yorker magazines. He has two brothers: David Preston (a medical doctor) and Richard Preston, also a best-selling fiction/non-fiction author.

Most of Preston's five nonfiction books and thirteen novel were bestsellers and have been translated into many languages. With his frequent collaborator, Lincoln Child, he has co-authored such bestselling thrillers as The Cabinet of Curiosities, The Ice Limit, Thunderhead, Riptide, Brimstone and Relic. Their novel, The Book of the Dead, which came out in June 2006, was on the New York Times bestseller list for six weeks. Preston writes about archeology for the New Yorker magazine and he has also been published in Smithsonian magazine, Harper's, and National Geographic. He is the recipient of numerous writing awards. He has created the character Wyman Ford, an ex-CIA agent who appears in many of his solo novels.

From 1978 to 1985, Preston worked for the American Museum of Natural History in New York City as a writer, editor, and manager of publications. He served as Managing Editor for the journal Curator and was a columnist for Natural History magazine. In 1985 he published a history of the museum, An Excursion into the American Museum of Natural History, which chronicled the explorers and expeditions of the museum's early days.

In 1986 Preston moved to New Mexico and began to write full-time. Seeking an understanding of the first moment of contact between Europeans and Indians in America, he retraced on horseback Francisco Vasquez de Coronado's violent and unsuccessful search for the legendary Seven Cities of Gold. That thousand mile journey across the American Southwest resulted in the book A Journey Across the American Southwest. Since that time Preston has undertaken many long horseback journeys retracing historic or prehistoric trails. He has also participated in expeditions in other parts of the world, including a journey deep into Khmer Rouge-held territory in the Cambodian jungle with a small army of soldiers, to be the first Westerner to visit a lost Angkor temple. He once had the thrill of being the first person in 3,000 years to enter an ancient Egyptian burial chamber in a tomb known as KV5 in the Valley of the Kings.

Preston counts in his ancestry the newspaperman Horace Greeley and the infamous murderer and opium addict Amasa Greenough. He and his wife, Christine, live in Maine with their three children.

Douglas Preston has been an outspoken critic of the Italian judicial system in the case of Amanda Knox, the American college student from Seattle convicted of murder in the November 2007 death of her British housemate, Meredith Kercher. While writing The Monster of Florence in 2006, Preston came into conflict with an Italian prosecutor, Giuliano Mignini, who was involved in both the Monster of Florence investigation and later in the Amanda Knox case.

Preston was prominently featured in an April 2009 segment of CBS 48 Hours where he termed the case against Ms. Knox as “based on lies, superstition, and crazy conspiracy theories.” Following the Knox verdict on December 4, 2009 he appeared on Anderson Cooper 360° and described his own interrogation by Mignini. Preston ridiculed Mignini and stated, “this is a very abusive prosecutor; he makes up theories; he’s obsessed with satanic sects.”

Fiction

• Jennie (1994)
• The Codex (2004)
• Tyrannosaur Canyon (2005)
• Blasphemy (2008)
• Impact (2010)

Non-fiction

• 1986 An Excursion into the American Museum of Natural History
• 1988 Death Trap Defies Treasure Seekers for Two Centuries
• 1992 Cities of Gold: A Journey Across the American Southwest in Pursuit of Coronado
• 1996 One Family's Journey on Horseback Across the Sacred Land of the Navajo
• 2004 We throw stones, not Quarks (essay that later became his solo novel "Blasphemy")

The Pendergast novels

• Relic (1995)
• Reliquary (1997)
• The Cabinet of Curiosities (2002)
• Still Life with Crows (2003)
• Diogenes Trilogy
• Brimstone (2004)
• Dance of Death (2005)
• The Book of the Dead (2006)
• The Wheel of Darkness (2007)
• Cemetery Dance (2009)
• Fever Dream (2010)

The Gideon Crew series

• Gideon's Sword (2011)

Other novels

• Mount Dragon (1996)
• Riptide (1998)
• Thunderhead (1999)
• The Ice Limit (2000)

Non-fiction

• The Monster of Florence (2008)