[2][3] The Wetherills lived on a 160 acres (65 ha) farm near Mancos, but husband John's main interest was the abundant remains of the ancient Puebloans in the area.

To supplement his income, he guided scholars to the ruins and to visit the many tribes of Native Americans (Indians) living on reservations in New Mexico and Arizona.

[4] In 1900, Richard Wetherill offered John the job of managing the Ojo Alamo Trading post, 20 miles (32 km) northwest of the ancient Puebloan ruins in Chaco Canyon, New Mexico.

In November 1900, the Wetherill family and their long-time partner, Clyde Colville, journeyed to Ojo Alamo ("Cottonwood Tree Spring") by horse-drawn wagon and became the only Anglo people in a large desert area.

John was away a good deal of the time pursuing his interests, and Louisa was left managing the trading post.

[8][9][10] To establish their trading post the Wetherill's secured the permission of a wealthy local Navajo chief named Hoskinini.

[11][12] In 1910, the Wetherill's moved and established a new trading post at Todanestya, "the place where water runs like fingers out of a hill," 20 miles (32 km) south of Oljato.

[14] One of the visitors was Theodore Roosevelt in 1913 who said of Louisa and the Navajo: "Mrs. Wetherill was not only versed in archaeological lore concerning ruins...she...knows their language; she knows their minds; she has the keenest sympathy not only with their bodily needs, but with their mental and spiritual processes.

[17][18] Beginning in 1921, Wetherill made several trips to Mexico to investigate a theory that several Navajo clans had migrated northward in pre-Columbian times.

The Wetherills began to spend the winters in southern Arizona and established the Rancho de la Osa Guest Ranch in Sasabe in 1926.

When her two children grew up, Wetherill fostered three Navajo girls from the Tuba City Boarding School: Esther, Fannie, and Betty Zane.

According to her foster daughter Betty, Wetherill ensured the ending of the abuse happening in the boarding school before taking the girls home with her.

When her husband and his business partner died within half a year in 1944 and 1945 Wetherill sold the trading post and moved to a ranch owned by her son, Benjamin, in Skull Valley, Arizona.