Applegate was born in Atlanta, Georgia. He studied at the University of Illinois under F.F. Frederick, the Pennsylvania Academy of Fine Arts and at the Academie Julian in Paris. He taught at the School of Industrial Arts in Trenton, New Jersey.
He settled in Santa Fe, New Mexico in 1921; He immediately began working to preserve Santa Fe's culture and architecture through his art, the building and renovation of homes and his writings as well as his passion for Spanish Colonial devotional art . The first home he built on Camino del Monte Sol is hailed as one of the city's finest examples of Spanish-Pueblo Revival architecture. Applegate immersed himself in the culture and traditional art forms of the region, amassing a great deal of knowledge as well as an impressive collection of local devotional art. This is reflected in his work with a shift in his paintings and drawings as well as inspiring him to create furniture and Santos.
Applegate became a member of the New Mexico Painters Society and, along with Mary Austin, founded the Spanish Colonial Arts Society.

In 1929, he published the book, "Indian Stories from the Pueblos."

Around 1928, Applegate and Austin began work on a book on the Spanish Colonial arts of New Mexico and Ansel Adams joined the effort photographing the objects. During this period, Adams took an iconic photograph of Applegate with a cigarette and his sketchbook. Sadly, the book did not come to fruition as Applegate died in 1931 and Austin was unable to publish the book prior to her own death in 1934.

Refer to: Frank Applegate of Santa Fe: Artist & Preservationist by Daria Labinsky and Stan Hieronymus