Judy Sanders (Robin Frates), an employee of a genetic research facility named EMAX, contacts television personality Lori Tanner (Ally Sheedy), planning to meet after work so she can show Lori the atrocities and animal cruelty that go on in EMAX's laboratories. As she proceeds back to work, an animal assailant attacks and kills her. Dr. Jarret (Lance Henriksen), a scientist performing vivisection and genetic altering and the owner of EMAX, comes in and shoots the animal with a sedative to stop the attack. Later, Lori arrives at EMAX. When Judy does not appear, she breaks into the laboratory and films the various animals that are being experimented on. She discovers a Tibetan Mastiff named Max who does not appear to have been experimented on and lets the dog out of his cage. Dr. Jarret discovers that there is an intruder in the laboratory and chases Lori out of the building, with Max following Lori into her car as she drives away. Jarret immediately goes to the police and complains that his dog has been stolen. Later that day, when Lori goes shopping, a mugger (Thomas Rosales, Jr.) steals her purse. Max chases the thief, brutally kills him, and brings Lori's purse back to her.
Unaware that the dog has killed the mugger, Lori develops a bond with Max, feeling protected with him around and decides to keep him. However, her boyfriend Perry (Fredric Lehne) initially refuses to allow Lori to keep the dog, despite his heroic actions. He finally agrees to let Max stay, but only if he stays in the backyard. However, Max can understand human conversations and becomes overprotective of Lori. He later finds Lori and Perry having sex in their bedroom and tries to attack Perry, understanding that Perry isn't too fond of him.
Dr. Jarret is questioned by detectives Frankie Kovacs (Robert Costanzo) and Emilio Bendetti (John Cassini) about Max. Jarret reveals that Max is a genetically altered dog, spliced with the DNA of various other animals such as big cats, snakes, chameleons, and birds of prey giving him enhanced strength, speed, and senses. Max is also prone to violent rages, and Jarrett regularly gives him a drug to keep him relaxed, but he fears that it won't be long before the effects of the drug wear off.
Max acts as a loyal, obedient, and lovable dog to Lori, but when her back is turned he starts wreaking havoc in the neighborhood, terrorizing some local children (though he seems all right with Lori's young neighbor Rudy), devouring a cat, destroying the brake lines in Perry's truck, mating with a neighbor's collie Heidi, and murdering a mail man (Rick Barker). All of these incidents go unnoticed by Lori. Realizing Max gnawed through the brake lines of his truck in an attempt to kill him, Perry tries to kill Max by feeding him poisoned hamburger. He tries to convince Max to eat it but Max smells the poison in the meat and chases Perry out of the house. After Perry escapes in his truck, Max eats Lori's talking pet parrot, who begins berating him. Max proceeds to dump the poison ridden hamburger in the toilet and flushes it.
Noticing Perry's animosity towards their new dog, Lori decides to find Max a new home. She takes him to a junkyard and leaves him with the owner Ray (William Sanderson), who assures her that Max will be taken to a ranch in a few days. However, when Lori leaves, Ray chains Max to the wall and hits him over the head with a shovel, knocking him out. When Max wakes up, he pulls loose from his chain and attacks Ray. Unfortunately, Ray arms himself with a blow torch and burns Max's face, but right as he is about to get his gun, he is soon overpowered and killed. Max, now severely scarred, leaves the junkyard and makes his way back to Lori's house. The police, after discovering the dead mugger and having Dr. Jarret clarify that it was Max who killed him, now intend to stop Max at any cost. By the time Max returns to Lori's, Perry has replaced him with a new puppy named Spike. Max, feeling betrayed, confronts Perry and burns his face with acidic urine, much to Lori's horror and realization. Max attempts to attack Lori and the neighbor kid but the police arrive to apprehend Max. Max then escapes out of the house and evades the cops and an animal control unit by utilizing his genetic gifts.
As an ambulance takes Perry away, the police demand Lori's help to catch Max and wait for him. Max arrives and kills the police watching the house, which Lori soon discovers. In an attempt to get him back, Jarret kidnaps Lori and her new dog Spike in hopes that Max will follow, which he does. Jarret drives back to the EMAX building, telling Lori that Max will turn on her as he did to Jarret. Max then chases them and attacks, jumping onto the car and causing it to crash. Lori pulls herself free from the car and grabs Spike as well. Upon realizing that Max is still alive, she runs into the building with Max chasing her into the laboratory where she first discovered him. She grabs a knife to protect herself as Max stalks her through the laboratory. In a final face to face confrontation, Lori realizes she isn't scared of Max, knowing he wouldn't hurt her and feels the bond they shared. Max watches as Lori puts down the knife and reaches out for him. Max relinquishes his aggressive, homicidal nature and begins to kiss her hand. Dr. Jarret, still alive, arrives with a pump-action shotgun and demands Lori move away from Max or he will kill them both. Lori refuses to move out of the way and Max breaks out of her grasp to protect her by taking the shot to the chest and pushing Dr. Jarret onto a large electrical cage. Spike begins to play and bite the electrical outlet connected to the cage, sparking it which begins electrocuting Jarret and killing him instantly. Lori rests Max's head on her lap and pets him as he dies and proceeds to mourn for him.
Three months later, Lori is going for a walk with Spike when Rudy tells Lori that she has just had puppies and invites her to see them. Most of the puppies look like their mother with the one exception being a small black puppy that resembles Max, implying that this puppy has inherited Max's genetic altering....or at least his father's attitude.Ally Sheedy as Lori Tanner, a TV personality who becomes Max's adoptive owner.
Lance Henriksen as Dr. Jarret, a scientist at EMAX who is Max's original owner and tormentor.
Robert Costanzo as Detective Frankie Kovacs, a detective who investigates Max.
Fredric Lehne as Perry, Lori's boyfriend and Max's arch-rival. Max's second tormentor and near victim.
John Cassini as Detective Emilio Bendetti, a detective who investigates Max
J.D. Daniels as Rudy, Lori's young next-door neighbor.
William Sanderson as Ray, a junkyard operator, Max's fifth tormentor and victim.
Trula M. Marcus as Annie
Robin Frates as Judy Sanders, an employee at EMAX who is killed by Max.
Frank Welker as the vocal effects of Max, a genetically altered Tibetan Mastiff and also Ed, a parrot owned by Perry.
Rick Barker as Mailman, Max's fourth tormentor and victim.
Mickey Cassidy as Paperboy, Max's third tormentor.
Thomas Rosales, Jr. as Mugger, a man who robs Lori and becomes Max's second victim.
At least five different dogs were used in filming.
Kevin Yagher built the Max puppets as well as created the make-up special effects.
Additional tag lines for the film include "Companion. Protector. Killer." "He'll bite the hand that feeds him...And then he'll eat the rest." and "His bark isn't half as bad...as his bite!"
Man's Best Friend currently has a 20% approval rating on Rotten Tomatoes. Despite this, Ally Sheedy was nominated for a Saturn Award for Best Actress. Film critic Leonard Maltin gave it a moderately positive two-and-a-half-star review, calling it "derivative, but fun."
New Line Home Video released the film on DVD on September 6, 2005.Man's Best Friend is seen in the cult film Friday, another New Line Cinema film. Being watched by John Witherspoon's character, the scene shown is of a mailman being chased by the genetically-engineered dog.