Before the arrival of Euro-Americans in the 19th century, the John Day basin was frequented by Sahaptin people who hunted, fished, and gathered roots and berries in the region.

The monument has more than 80 soil types that support a wide variety of flora, ranging from willow trees near the river to grasses on alluvial fans to cactus among rocks at higher elevations.

Large mammals like elk and smaller animals such as raccoons, coyotes, and voles frequent these units, which are also populated by a wide variety of reptiles, fish, butterflies, and other creatures adapted to particular niches of a mountainous semi-desert terrain.

Located in rugged terrain in the counties of Wheeler and Grant, the park units are characterized by hills, deep ravines, and eroded fossil-bearing rock formations.

[7] The remaining 8,843 acres (3,579 ha)[n 1] of the park, the Sheep Rock Unit, are located along Oregon Route 19 and the John Day River upstream of the unincorporated community of Kimberly.

[13] Bridge Creek passes through Mitchell, then north along the eastern edge of the Painted Hills Unit to meet the John Day downstream of Twickenham.

[7][13] Early inhabitants of north-central Oregon included Sahaptin-speaking people of the Umatilla, Wasco, and Warm Springs tribes as well as the Northern Paiutes, speakers of a Uto-Aztecan (Shoshonean) language.

[14] Researchers have identified 36 sites of related archeological interest, including rock shelters and cairns, in or adjacent to the John Day Fossil Beds National Monument.

[17] After passage of the Homestead Act of 1862 and the discovery of gold in the upper John Day basin, a fraction of these newcomers abandoned the Willamette Valley in favor of eastern Oregon.

[17] Settlement was made more practical by a supply route from The Dalles on the Columbia River to gold mines at Canyon City in the upper John Day valley.

[17] In 1864, a company of soldiers sent to protect mining camps from raids by Northern Paiutes discovered fossils in the Crooked River region, south of the John Day basin.

Condon's trips to the area and his public lectures and reports about his finds led to wide interest in the fossil beds among scientists such as Edward Drinker Cope of the Academy of Natural Sciences.

During the first half of the 20th century, scientists such as John C. Merriam, Ralph Chaney, Frank H. Knowlton, and Alonzo W. Hancock continued work in the fossil beds, including those discovered near Clarno in about 1890.

[32] The John Day Fossil Beds National Monument lies within the Blue Mountains physiographic province, which originated during the late Jurassic and early Cretaceous, about 118 to 93 million years ago.

[33] Northeastern Oregon was assembled in large blocks (exotic terranes) of Permian, Triassic, and Jurassic rock shifted by tectonic forces and accreted to what was then the western edge of the North American continent, near the Idaho border.

[34] By the beginning of the Cenozoic era, 66 million years ago, the Blue Mountains province was uplifting (that is, was being pushed higher by tectonic forces), and the Pacific Ocean shoreline, formerly near Idaho, had shifted to the west.

[35][n 4] Volcanic eruptions about 44 million years ago during the Eocene deposited lavas accompanied by debris flows (lahars) atop the older rocks in the western part of the province.

[39] The Clarno Formation also contains bones, palm leaves longer than 24 inches (61 cm), avocado trees, and other subtropical plants from 50 million years ago,[40][41][42] when the climate was warmer and wetter than it is in the 21st century.

[48] One of the notable plant fossils is the Metasequoia (dawn redwood), a genus thought to have gone extinct worldwide until it was discovered alive in China in the early 20th century.

[49] After another period of erosion, a series of lava eruptions from fissures across northeastern Oregon, southeastern Washington, and western Idaho inundated much of the Blue Mountain province with liquid basalt.

Extruded in the middle Miocene between 17 and 12 million years ago, more than 40 separate flows contributing to the Columbia River Basalt Group have been identified, the largest of which involved up to 400 cubic miles (1,700 km3) of lava.

[50] Subsequent ashfall from eruptions in the Cascade Range in the late Miocene contributed to the Mascall Formation, layers of stream-deposited volcanic tuffs laid atop the Picture Gorge Basalt.

[51] Preserved in the Mascall are fossils of animals such as horses, camels, rhinoceroses, bears, pronghorn, deer, weasels, raccoons, cats, dogs, and sloths.

Western junipers, which have extensive root systems, thrive in the dry climate; in the absence of periodic fires they tend to displace grasses and sagebrush and to create relatively barren landscapes.

[68] Wildflowers, which bloom mainly in the spring and early summer, include pincushions, golden bee plant, dwarf purple monkey flower, and sagebrush mariposa lily at the Painted Hills Unit.

Munro's globemallow, lupines, yellow fritillary, hedgehog cactus, and Applegate's Indian paintbrush are commonly seen at the Clarno and Sheep Rock units.

Species observed at the Sheep Rock Unit also include those able to tolerate warm summer river temperatures: bridgelip suckers, northern pikeminnow, redside shiners, and smallmouth bass.

The Park Service has removed or replaced irrigation diversions along the river or Rock Creek that formerly impeded fish movement, and it is restoring riparian vegetation such as black cottonwood trees that shade the water in summer and provide habitat for aquatic insects.

[78] Entrance to the park and its visitor center, museums, and exhibits is free,[79] and trails, overlooks, and picnic sites at all three units are open during daylight hours year-round.

[87] Ranger-led events at the monument have historically included indoor and outdoor talks, showings of an 18-minute orientation film, hikes in Blue Basin, Cant Ranch walking tours, and astronomy programs at the Painted Hills Unit.