I-25 begins at I-10's exit 144 in Las Cruces (elevation 4,000 feet (1,200 m)),[3] just south of the New Mexico State University (NMSU) campus.

Before I-25 reaches Truth or Consequences and just south of Elephant Butte Reservoir State Park, it crosses over to the west side of the Rio Grande.

After Bernalillo, I-25 passes through four more Indian Reservations (from south to north: the Pueblos of Santa Ana, San Felipe, Kewa, and Cochiti).

I-25 turns to the northeast and away from the Rio Grande, alongside which it has run from its southern terminus, as it heads toward Santa Fe.

[15] It climbs out of the Rio Grande Valley at a steep hill called La Bajada 11 miles (18 km) southwest of Santa Fe.

[18] The highway maintains a north and northeast orientation as it leaves New Mexico traversing Raton Pass (7,798 feet (2,377 m)[19]) and enters Colorado.