U.S. Route 66 in Arizona covered 401 miles (645 km) between Needles, California and the New Mexico border as part of the historic U.S. Route 66 from Santa Monica to Chicago. The highway was decommissioned in 1985 although portions remain as Arizona State Route 66.

In 1914 the road was designated "National Old Trails Highway"; in 1926 it was re-designated as U.S. Route 66. One section just outside Oatman, Arizona (through the Black Mountains) was fraught with hairpin turns and was the steepest along the entire route, so much so that some early travellers, too frightened at the prospect of driving such a potentially dangerous road, hired locals to navigate the winding grade. The section remained as Route 66 until 1953, and is still open to traffic today as the Oatman Highway.

On October 13, 1984, Williams, Arizona was the last point on U.S. Route 66 to be bypassed by an Interstate highway. US 66 was dropped from the US Highway system in 1985; parts of the highway were either absorbed into I-40, turned over to the state (SR 66), or turned over to Yavapai County.

Route 66 entered Arizona from Needles, California across the Topock Gorge, within the Havasu National Wildlife Refuge,

Between the California state line and Kingman, the original alignment is now known as Oatman Road and passed through the old mining town of Oatman, now a ghost town due to mine closures. A later alignment (via Yucca) is now Interstate 40. The older alignment passes through the Black Mountains complete with numerous hairpin turns. This area is desert.

Arizona State Route 66 is the only part of old US 66 in Arizona to have state route markers. It still serves communities that the freeway avoids, including Valentine, Hackberry and Peach Springs; it enters the Hualapai Indian Reservation. Its western terminus is near Kingman at exit 52 on Interstate 40 and its eastern terminus was originally near Seligman at exit 123 on Interstate 40. The state highway designation currently covers just 66 miles (106 km) of a section east of Kingman. The road continues east into Yavapai County as a county-maintained road as the state turned over the easternmost 16.8 miles (27.0 km) of SR 66 (known as Crookston Rd) to Yavapai County in 1990 for maintenance.

Between Kingman and Seligman, Interstate 40's more southerly and more direct path diverges from US 66 by approximately 16 miles (26 km), cutting off businesses on this section from highway traffic on the freeway's completion. Hackberry became a ghost town; at one point artist Bob Waldmire (owner of the Hackberry General Store from 1992-1998) was its only resident.

The Grand Canyon Caverns, just east of Peach Springs, are among the largest of dry caverns in the United States.

Seligman is the birthplace of the first route 66 association, established by local barber Angel Delgadillo in 1987. This group obtained the first "Historic Route 66" designation, which the state initially placed on the segment of U.S. Route 66 between Kingman and Seligman.

From Seligman to east of Flagstaff, the area is mountainous (not desert) and covered with pine forests. The old section through Flagstaff itself is officially named "Route 66". Shortly before joining I-40 east of Flagstaff, US 66 passes through Winona, a small unincorporated community made famous in the song "(Get Your Kicks on) Route 66".

Several abandoned portions of the former US 66 highway are listed on the National Register of Historic Places. These include Abandoned Route 66, Ash Fork Hill, Abandoned Route 66, Parks (1921) east of Parks, Arizona and Abandoned Route 66, Parks (1921) west of Parks, Arizona. Two Guns, Arizona is part of the railroad ghost town of Canyon Diablo.

The Meteor Crater is south of old US 66 at Meteor City. The Homolovi State Park near Winslow preserves over 300 Ancestral Puebloan archaeological sites. At Joseph City is the Jack Rabbit Trading Post, which once posted signs up and down the highway for hundreds of miles, and at Holbrook is the Wigwam Village Motel, a motor court built to resemble a group of teepees. The Petrified Forest National Park is located east of Holbrook. About sixty miles before reaching New Mexico, the highway originally passed through the Painted Desert, though this section is now cut off.

Portions of US 66 were paved over by Interstate 40 construction or converted to frontage roads.

The original 378 miles (608 km) route (as listed) goes through Oatman, Arizona and was in use before 1953. A later route through Yucca, Arizona (now part of Interstate 40) is longer at 401 miles (645 km) but avoids mountains and hairpin turns east of Mohave Valley, bypassing Oatman.

A Desert Power & Water Co., Electric Power Plant built in 1908 closed in 1938, soon after the Hoover Dam was completed; it now houses a visitor information office and Kingman, Arizona's chamber of commerce.

The Schoolhouse at Truxton Canyon Training School in Valentine operated from 1903-1937 as a mandatory boarding school in which Hualapai were separated from their families and put to work learning various trades. Long a symbol of forced assimilation, the historic building is now the property of the Hualapai Nation.

The Peach Springs Trading Post, constructed in 1928 using local stone and logs, replaced an earlier 1917 trading post at Peach Springs. Its original role was to trade native crafts for foodstuffs, medicine and household goods. The building now houses Hualapai conservation offices.

Lowell Observatory, an astronomical observatory established in Flagstaff in 1894, is one of the oldest observatories in the United States and a designated National Historic Landmark. Flagstaff's Santa Fe Railroad Depot, built in 1926, is the busiest of the eight Arizona Amtrak stations and includes a visitor information office. Flagstaff's 43-room Hotel Monte Vista was established in 1927.

Delgadillo's Snow Cap Drive-In in Seligman, built in 1953 with scrap railway lumber by Juan Delgadillo (May 17, 1916 - June 2, 2004), continues to offer choices such as a "cheeseburger with cheese" and "dead chicken."

The Oatman Hotel, a historic two-story adobe building which opened in 1902 as the Durlin Hotel and was rebuilt in 1924 during a local gold rush, now houses a bar, restaurant and museum.

The Wigwam Village Motel in Holbrook is distinctive for patented novelty architecture in which every room of the motel is a free-standing concrete wigwam. In Pixar's 2006 animated film Cars, these are depicted as the traffic cones of the Cozy Cone Motel.

The Pueblo Revival style Painted Desert Inn in Navajo, constructed circa-1920 of wood and native stone and purchased by the US National Park Service in 1935, is situated on a mesa overlooking the vast Painted Desert.