The historic U.S. Route 66 (US 66) ran east–west across the central part of the U.S. state of New Mexico, along the path now taken by Interstate 40. However, until 1937, it took a longer route via Los Lunas, Albuquerque, and Santa Fe, now roughly NM 6, I-25, and US 84. Large portions of the old road parallel to I-40 have been designated State Road 118 (NM 118), State Road 122 (NM 122), State Road 124 (NM 124), State Road 333 (NM 333), three separate loops of Interstate 40 Business, and state-maintained frontage roads.

Route 66 in New Mexico was marked over portions of two auto trails â€” the National Old Trails Road from Arizona via Albuquerque and Santa Fe to just shy of Las Vegas, and one of the main routes of the Ozark Trails network from that point into Texas. The state had taken over maintenance of these roads under several numbers: State Road 6 from Arizona to Los Lunas, part of State Road 1 through Albuquerque and Santa Fe to near Las Vegas, State Road 56 to Santa Rosa, the short State Road 104 to Cuervo, and part of State Road 3 to Texas. While NM 56 and NM 104 were completely absorbed by US 66, NM 6 was reassigned to a route splitting from US 66 (old NM 6) at Laguna and heading straight east through Albuquerque, Moriarty, and Palma to US 66 at Santa Rosa. Except between Albuquerque and Moriarty, where it formed part of U.S. Route 470, this was an unimproved road.

This new NM 6 was approved as a future realignment of Route 66 by 1932, and in 1933 a new bridge over the Rio Puerco opened. Once paving was completed in 1937, with AASHO approval given on September 26, 1937, Route 66 was moved to this shorter route, known as the Laguna Cut-off west of Albuquerque and the Santa Rosa Cut-off east of Albuquerque. The bypassed roads became NM 6 once again to the west and part of US 84 to the east.[citation needed]

From the Arizona state line to the Grants area is mountainous, and US 66 meanders around I-40. It also passes through some Indian reservations. At Laguna, New Mexico is the Laguna Indian Pueblo.

At Mesita, the highway originally followed what is now NM 6 to east of I-25 at Los Lunas. It passed through Albuquerque from south to north along Fourth Street, part of the historic El Camino Real de Tierra Adentro (El Camino Real). The highway is now replaced with I-25 through Santa Fe to, almost, Las Vegas (Historic 66 turns south before reaching Las Vegas), though several old sections exist which are barely (if at all) driveable. From south of Las Vegas back to I-40, the road has been replaced with US 84.

The later alignment (and more popular) continued straight west to Albuquerque, becoming Central Avenue through the city. While the former US-66 route through Albuquerque is now owned and maintained by the city of Albuquerque, a few US-66/BUSINESS I-40 signs remain along Central Avenue in the downtown area. East of Albuquerque, US 66 is now NM 333 all the way to Moriarty. Interstate 40 east of Moriarty to Santa Rosa was built by adding a second set of lanes to US 66. East of Santa Rosa, US 66 is now largely frontage roads for I-40 or business loops for Santa Rosa and Tucumcari. At San Jon, the original alignment (now gravel) continues to the Texas state line at the historic ghost town of Glenrio. A later alignment is the north frontage road for I-40.

This route is based on the later alignment via Central Avenue in Albuquerque, bypassing both Santa Fe and Los Lunas. Much of this road was upgraded in place as I-40 or used as frontage road or business loops.

The New Mexico Madonna of the Trail is one of a dozen monuments (one in each state on the National Old Trails Road) commemorating the hardships of early pioneer travellers. She stands on US 66 in Albuquerque. Albuquerque is also home to the 1927 Art Deco KiMo Theater and the first modern suburban shopping mall in New Mexico, Nob Hill.

Fort Wingate, an abandoned military installation east of Gallup, traces its history to attempts in the 19th century to forcibly displace Navajo to native reservations. It later served as a line of defence against the Apache. Closed in 1912, it reopened briefly to house prisoners during two world wars.

The Barelas-South Fourth Street Historic District is a collection of commercial buildings from various eras in a formerly Hispanic residential neighbourhood in Albuquerque. Eras represented include the arrival of the Atchison, Topeka and Santa Fe Railway and the later construction of US Route 66.

The Park Lake Historic District is a 25-acre municipal park on a lake in Santa Rosa. Constructed under the Works Progress Administration between 1934 and 1940, the park was a make-work project during the Great Depression.

The historic Jones Motor Company building in Albuquerque, originally a motorcar dealership, has been re-purposed to house Kelly's Brew Pub.

Richardson's Store in Montoya, a 1901 railroad town, initially provided provisions for Rock Island Railroad workers and ranchers. When Route 66 came to town, the store carried groceries and auto supplies. It closed after Interstate 40 bypassed the community.

Roy T. Herman's Garage and Service Station in Thoreau was moved in 1937 from Grants, where it had originally been established in 1935. The routing of Route 66 had moved, so the station moved with it to keep its Route 66 clientele.

New Mexico is home to the Native American Pueblo of Santo Domingo (Kewa Pueblo) in Santo Domingo and the Pueblo of Laguna in Laguna. Roadside merchants on Route 66 often based their stores on the design of the early trading posts which originally served the native community.

Bowlin's Old Crater Trading Post, Bluewater has long been closed and vacant. Originally a native trading post, its proprietors established a modern chain of highway service centres. Albuquerque's 1939 Maisel's Indian Trading Post, which once employed hundreds of native craftspeople, was reopened in the 1980s and remains in operation today.

Various towns and cities quickly established roadside motel strips to accommodate a burgeoning traffic from Route 66 travellers.

Tucumcari had long advertised "2000 motel rooms" (later "1200 motel rooms") on roadside signage for hundreds of miles along US 66 using the slogan "Tucumcari tonite!" At least one historically-restored Tucumcari Boulevard motel, the 14-room neon-lit 1939 Blue Swallow Motel, is listed on the National Register of Historic Places.

Central Avenue in Albuquerque has many motels from this era, although some (such as the Aztec Motel) have been demolished. Historic Albuquerque lodgings from Route 66's heyday include the Luna Lodge, Tewa Motor Lodge, De Anza Motor Lodge and El Vado Auto Court. Some of these motels are currently closed but are the target of local efforts to ensure their historic preservation.

The El Rancho Hotel in Gallup has been the temporary home of many movie stars.

The Rio Puerco Bridge, a Parker Through truss bridge crossing the Rio Puerco, was built in 1933. Various New Mexico road segments on US 66 are listed on the National Register of Historic Places; some originally incorporated wooden bridges to carry the road through flood plains.