Along with George Plimpton, Harold L. Humes, Thomas Guinzburg and Donald Hall, Matthiessen founded the literary magazine The Paris Review in 1953. At the time he was working for the CIA.

In 1959, he published the first edition of Wildlife in America, a history of the extinction and endangerment of various animal and bird species at the hands of the human settlements that occurred throughout North American history, as well as historical efforts at endangered species protection. It was one of the first books to call attention to global warming, by mentioning how the polar ice cap formations caused the lowering of the seas, and how the isthmus that Mongoloid people crossed from Asia to present-day Alaska to establish North America's first settlement is now submerged by the Bering Strait.

In 1965, Matthiessen wrote a novel about a group of American missionaries and a South American tribe. The book was later made into a major Hollywood film with the same title, At Play in the Fields of the Lord, in 1991. In 1979, Matthiessen's nonfiction book The Snow Leopard won the Contemporary Thought category of the National Book Award. His work on oceanographic research, "Blue Meridian," with photographer Peter A. Lake, documented the making of the film "Blue Water, White Death," which was directed by Peter Gimbel and Jim Lipscomb. This is widely considered to have inspired Peter Benchley to write Jaws in 1974. Matthiessen has been the official State Author of New York, 1995-1997.

In 2008, Matthiessen revisited his trilogy of novels -- Killing Mr. Watson, Lost Man's River and Bone by Bone, based on accounts of Florida planter Edgar J. Watson's death shortly after the Southwest Florida Hurricane of 1910. He revised and edited the three books, which originated as one 1,500-page manuscript, and the result was a single volume entitled Shadow Country. The book won the 2008 National Book Award.

Shortly after the 1983 publication of In The Spirit of Crazy Horse, Matthiessen and his publisher Viking Penguin were sued for libel by FBI agent David Price and former South Dakota governor William J. Janklow. The plaintiffs sought over $49 million in damages; Janklow also successfully sued to have all copies of the book withdrawn from bookstores.After four years of litigation, Federal District Court Judge Diana E. Murphy dismissed Price's lawsuit, upholding Matthiessen's right "to publish an entirely one-sided view of people and events." In the Janklow case, a South Dakota court also ruled for Matthiessen. Both cases were appealed. In 1990, the Supreme Court refused to hear Price's arguments, effectively ending his appeal; the South Dakota Supreme Court dismissed Janklow's case the same year. With the lawsuits settled, the paperback edition of the book was finally published in 1992.

In his book The Snow Leopard, Matthiessen reports having a somewhat tempestuous on-again off-again relationship with his wife Deborah, culminating in a deep commitment to each other made shortly before she was diagnosed with cancer. She died in New York City near the end of 1972. She and Matthiessen had four children; the youngest of them, Alex Matthiessen, was 7 or 8 years old at the time of her death. In September of the following year, Matthiessen went on an expedition to the Himalayas with field biologist George Schaller.

Matthiessen and Deborah practiced Zen Buddhism. Matthiessen later became a Buddhist priest of the White Plum Asanga. Before practicing Zen, Matthiessen was an early pioneer of LSD. He says his Buddhism evolved fairly naturally from his drug experiences.

In 1980, Matthiessen married Tanzanian-born Maria Eckhart in a Zen ceremony on Long Island, New York. They live in Sagaponack, New York.

In 2005, Matthiessen along with Barry Lopez, Terry Tempest Williams, and James Galvin, was hailed in Mark Tredinnick's The Land's Wild Music in which Tredinnick analyzed how the landscape nourished and developed Matthiessen's writing.

Fiction

• Race Rock (1954)
• Partisans (1955)
• Raditzer (1961)
• At Play in the Fields of the Lord (1965)
• Far Tortuga (1975)
• On the River Styx and Other Stories (1989)
• Killing Mister Watson (1990)
• Lost Man's River (1997)
• Bone by Bone (1999)
• Shadow Country (2008) (a new rendering of the Watson trilogy)

Nonfiction

• Wildlife in America (1959)
• The Cloud Forest: A Chronicle of the South American Wilderness (1961)
• Under the Mountain Wall: A Chronicle of Two Seasons in the Stone Age (1962)
• "The Atlantic Coast", a chapter in The American Heritage Book of Natural Wonders (1963)
• The Shorebirds of North America (1967)
• Oomingmak (1967)
• Sal Si Puedes: Cesar Chavez and the New American Revolution (1969)
• Blue Meridian. The Search for the Great White Shark (1971).
• The Tree Where Man Was Born (1972)
• The Snow Leopard (1978)
• Sand Rivers (1981)
• In the Spirit of Crazy Horse (1983) ISBN 0-14-014456-0
• Indian Country (1984)
• Nine-headed Dragon River: Zen Journals 1969-1982 (1986)
• Men's Lives: The Surfmen and Baymen of the South Fork (1986)
• African Silences(1991)
• Baikal: Sacred Sea of Siberia (1992)
• East of Lo Monthang: In the Land of the Mustang (1995)
• The Peter Matthiessen Reader: Nonfiction, 1959-1961 (2000)
• Tigers in the Snow (2000)
• The Birds of Heaven: Travels With Cranes (2001)
• End of the Earth: Voyage to Antarctica (2003)