In 1892 Edward married Clara J. Phillips and the couple would eventually have four children. In the bustling frontier city of Seattle, his photography business began to thrive. In 1895, he met and photographed Salish Princess Angeline, who was known by her tribe as Kickisomlo, the daughter of Chief Sealth of Seattle. This was to be his first portrait of a Native American. His favorite subjects beyond the confines of the studio were Mount Rainier, city scenes, and, increasingly, local Indians. He was also quick to follow the news, reporting on the hardships which befell the prospectors who joined the gold rush to the Klondike in 1897.

In 1898 while photographing Mt. Rainier, Curtis came upon a small group of scientists, one of whom was George Bird Grinnell, an expert on Native Americans. Both Grinnell and Curtis were invited on the famous Harriman Alaska Expedition in 1899, in which Curtis was designated as the official photographer Afterward, Grinnell invited Curtis to join an expedition to photograph the Blackfoot Indians in Montana in the year 1900.

During the expedition, Curtis witnessed the Sun Dance ceremonies, rituals of pain willingly suffered "for strength and visions." Through this experience together with Grinnell's tutelage, Curtis came to his developing conception of a comprehensive written and photographic record of the most important Indian peoples west of the Mississippi and Missouri Rivers who still, as he later put it, retained "to a considerable degree their primitive customs and traditions." Though he initially agreed with the U.S. Bureau of Indian Affairs, that Indians could not survive unless they forfeited their traditional lifeways and adapted to a new culture, over time, he grew to respond to the government's policy towards Indians with fierce anger.

In 1906 J.P. Morgan offered Curtis $75,000 to produce a series on North American Indians. The series was to be in 20 volumes with 1,500 photographs, with Morgan was to receiving 25 sets of the series and 500 original prints. During the work, Curtis took over 40,000 photographs from over 80 tribes. When completed, 222 sets were published, which not only held photographs; but, also documentation on Native American traditional life, biographical sketches, tribal lore and history, and descriptions of traditional foods, housing, garments, recreation, ceremonies, and funeral customs. In some cases, his documentation is the only recorded history. Edward's goal was to document the way of life before it disappeared, writing in the introduction to his first volume in 1907: "The information that is to be gathered ... respecting the mode of life of one of the great races of mankind, must be collected at once or the opportunity will be lost."