Like many of Picoult's novels, My Sister's Keeper was generally embraced by critics for its gripping exploration of emotionally complicated issues. For example, Tom Jackson of the Tampa Tribune represented the sentiments of many reviewers, declaring "My Sister's Keeper is a gut-wrenching, melancholic work designed to linger in the minds of its readers long after they have finished it." Others, such as Kim Uden Rutter of the Library Journal, called it "timely and compelling."

Many critics praised the way Picoult presents the story's dilemmas. Jennifer Reese of Entertainment Weekly commented, "My Sister's Keeper crackles when the characters wrestle with unanswerable moral questions." Similar sentiments were expressed on the Picoult's construction of the novel. While Andrea L. Sachs of People Weekly commented, "Picoult's style borders on the poetic," Robin Vidimos of the Denver Post noted, "It's a busy story, but Picoult keeps all the balls in the...