Saint-Gaudens was born in New York City to a French-born father, Bernard Paul Ernest Saint-Gaudens, and an Irish-born mother, Mary McGuiness, Louis received his early training as a cameo cutter from his brother, who later assisted him in beginning his art studies in Rome.

In 1878, he and his brother Augustus moved to Paris where they shared a studio and attended the École des Beaux-Arts from 1879 to 1880.

In 1898, he returned to the United States, where he settled in Flint, Ohio, and met his future wife, sculptor Annetta Johnson.

Their son, Paul Saint-Gaudens, was a master potter who became known for his Orchard Kiln Pottery Works.

His home and studio in Cornish, New Hampshire, a former Shaker Meetinghouse, were on the National Register of Historic Places until they were destroyed by fire in 1980.