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."

Others noted how carefully Lehane crafted his text. In Charleston, South Carolina's Post and Courier, Mindy Spar claimed, "Lehane has created a writer's crime novel. His style is almost poetic, and his descriptions convey feeling and detail without wasting a word."

Some critics found fault with Mystic River, including a few who admired his previous works. Bella English of the Boston Globe wrote, "Mystic River is neither as fast-paced nor as tightly written as his Kenzie-Gennaro series. Lehane fans no doubt will miss the chemistry between those two." While praising some aspects of Lehane's work, including his style and character development, Washington Post writer David Corn commented, "Lehane does a better job creating the threads than weaving them together."

Even the somewhat negative reviews had positive aspects to them, and most critics regarded Mystic River as an artistic triumph for Lehane. Thomas Mackin in World of Hibernia states, "Singular adjectives fail to capture the engrossing power of this murder mystery."