Stein sent copies to popular writers Arnold Bennett, H. G. Wells, George Bernard Shaw, and John Galsworthy, and hoped the book would be a commercial success. Sales were sparse, but the book was talked about in literary circles. William James, her psychology teacher at Johns Hopkins, called it "a fine new kind of realism".
Though restrained in comparison to the works to follow, the book was seen as radical in style. Writer Israel Zangwill wrote, "... I always thought [Stein] was such a healthy minded young woman, what a terrible blow this must be for her poor dear brother."
A reviewer for the Chicago Record-Herald wrote in early 1910 of the "analogous methods" of Stein and the subtle works of Henry James, who "presents us the world he knows largely through ... conversations"; Stein’s "murmuring people are as truly shown as are James' people who not only talk but live while they talk".
Stein sent copies of the book to African-American writers W. E. B. Du Bois and Booker T. Washington. African-American reactions to Stein's portrayal of Melanctha varied: novelist Richard Wright wrote that he could "hear the speech of [his] grandmother, who spoke a deep, pure Negro dialect", while poet Claude McKay "found nothing striking and informative about Negro life. Melanctha, the mulatress, might have been a Jewess."
Three Lives continues to be the most widely taught of Stein's books, considered more accessible than her later works, such as the "Cubist" Tender Buttons which followed in 1914.