It runs for approximately 670 miles (1,078 km) through the states of California, Oregon, and Washington, primarily serving interior areas on the east side of the Cascade Mountains.

Major cities on the US 97 corridor include Klamath Falls, Bend, and Redmond in Oregon; and Yakima, Ellensburg, and Wenatchee in Washington.

The highway travels northeast around Weed and into Shasta–Trinity National Forest, passing several lava fields as it ascends the northwest side of Mount Shasta.

It turns east at Haystack Butte and travels around Deer Mountain, crossing the shore of Grass Lake and serving a rest area.

[6][7] The highway descends from Mount Hebron and leaves the national forest to travel northeast across the Butte Valley, a rural area with few settlements.

[8][9] The highway passes through Dorris on a series of city streets and continues northeast to cross into Oregon near a junction with California State Route 161 northwest of Indian Tom Lake.

It travels north across the Crooked River National Grassland to Madras, where the highway is concurrent with US 26 and splits into a pair of one-way streets.

The two highways travel parallel to each other on opposite sides of the Deschutes River canyon, with US 197 to the west serving The Dalles and US 97 to the east passing through the sparsely-populated area between Shaniko and Wasco.

[14][15] The southernmost section between the California state line and Klamath Falls is part of the Volcanic Legacy Scenic Byway, which continues to Crater Lake;[10] the northernmost section between Shaniko and Biggs Junction is part of the Journey Through Time Scenic Byway, which continues east through John Day Fossil Beds National Monument.

[16] The highway enters Washington at Maryhill, a community on the north side of the Columbia River that is home to a state park and Stonehenge replica.

US 97 then turns northwest at a junction with SR 22 in Toppenish and travels through Wapato before leaving the Yakima Indian Reservation and merging with I-82 and US 12 at Union Gap.

[17] The highway bypasses Wenatchee and crosses the Columbia River on the Richard Odabashian Bridge before turning north onto a two-lane road at a junction with SR 28.

[17] SR 20 turns east at Tonasket while US 97 continues north to the Canadian border near Oroville and Osoyoos, where it terminates and becomes British Columbia Highway 97 (BC 97).

[22] During World War II, US 97 formed the eastern boundary of a restricted military zone for Washington and Oregon created in March 1942 ahead of the mass internment of Japanese Americans.

[35][36] Plans for other bypasses in La Pine and Madras, as well as four-laning the entire highway in Oregon, have been proposed but not funded by the state government.

[40][41] AASHO formally approved the Alaska extension of US 97 in December 1964, subject to the renumbering of highways in the Yukon Territory and British Columbia to match the "97" designation.