The earliest human remnants were left in Sedona by ancient peoples referred to collectively as the Desert Culture, from which sprang the Anasazi and Hohokam groups, among others. Anasazi is a Navajo name, which translates as "the ancient ones who are not us." Some researchers believe that the Hopi tribes are direct descendants of this culture.

The Sinagua, whose Spanish name means "without water," were a hardy agrarian society that dry farmed and traded extensively in the area from about 1100-1400 AD. Commerce was not limited to nearby tribes, but flourished as a hub, trading with groups from the Pacific coastal regions as well as from South America. Salt and copper were major exported items, while imports included exotic bird feathers from South America and shells from the West Coast. There are indications that tribes put aside differences for celebrations and religious ceremonies that took place in this region.

Traces of these ancient civilizations can be found hidden in the remains of the great pueblos that once housed them. The Palatki ruin, constructed by the Sinagua and located between Sedona and Clarkdale, offers glimpses of the past depicted through charcoal rock drawings of snakes and Kokopelli. Researchers believe that some of these pictographs were actually the identifying symbols of a particular family or clan. It is believed that as many as 50 people may have once resided in these two pueblos. Honanki, another nearby Sinaguan ruin, held as many as 60 rooms and the structure quality is considered world class.

Southeast of Sedona is Montezuma's Castle and nearby Montezuma's Well, fabulous examples of cliff dwellings that were also built by the Sinagua people in the same time period. The area was originally occupied by the Hohokam, who farmed the bottomland using a unique irrigation system that extended for more than a mile from the fresh springs of Montezuma's Well.

When the volcanic ash remains from an eruption farther north drew the Hohokam to more fertile lands, the Sinagua people settled in. Many changes took place for the people at this point; some theorize that they borrowed masonry techniques from the Anasazi to the north, building above ground dwellings for the first time. The Sinagua also began using the irrigation techniques of the Hohokam. Early in the 15th century, these people vanished from the area for reasons unknown today.