Holmes was born January 21, 1887, in Lincoln, Maine to a poor family. Holmes left Maine for Boston, Massachusetts when at age 15 and, at the age of 21, he took a two-year course in public speaking at the School of Expression, where he was introduced to Mary Baker Eddy's Science and Health.

In 1912 Holmes joined his brother Fenwicke in Venice, California. There Ernest and his brother, a Congregationalist minister, studied the writings of Thomas Troward, Ralph Waldo Emerson, William Walker Atkinson, and Christian D. Larson.

In the 1920s, Holmes published the following statement of beliefs:

Through his research, Holmes created a "structure of concepts" based on the religions and philosophies of human history , sometimes correlating his findings with the then-emerging "new" physics. He named the teaching a science because he believed that its principles were scientifically provable in practice. He wrote, "I would rather see a student of this Science prove its Principle than to have him repeat all the words of wisdom that have ever been uttered."

Holmes ultimately came to believe in a "core concept" -- what he saw as a "Golden thread of truth" that ran through all of the world's religions as well as in science and philosophy.