Mystic River is regarded by many critics as Lehane's breakthrough novel, and it received generally positive reviews. Though the author had seen success with his five previous novels, a crime fiction series featuring the detectives Angie Gennaro and Patrick Kenzie, Mystic River is widely regarded as being of a higher quality than his Gennaro-Kenzie books. Critics praised many literary elements of the novel, including character, setting, and writing style. Carol Memmott of USA Today wrote, "Lehane has let loose with a standalone novel of depth and fervent passion."

A particular aspect of Mystic River that a number of critics commented on was the complexity of his characters. David Pitt wrote in Booklist, "Lehane is one of the small group of crime writers whose novels reveal a deep fascination with people, with motivation and inner turmoil and the subtle things that make characters walk off the page...