Under these cover stories, John and Jane balance their apparently mundane marriage which both of them find after a few years to be growing dull and suffocating with their secretive work. When both are assigned to kill Benjamin "The Tank" Danz (Adam Brody), they encounter each other on the job and botch the hit. Believing each had been sent to stop the other from completing their mission, they seek to discover and eliminate the other.
After a few "mild" attempts on each other's lives, fueled by a mutual sense of betrayal, the marital spat culminates in a high-octane fight in the Smith house. After a long, evenly-matched fight, with their house shot to shambles, they wind up with guns in each other's faces. John balks, and lays his gun down; Jane finds she cannot shoot her spouse either, and both succumb to their love instead. Mr. and Mrs. Smith reunite and rediscover each other.
The newly-rekindled Smith partnership is quickly threatened by their employers, who have now decided to eliminate the couple. John's best friend and coworker, Eddie (Vince Vaughn), turns down a bounty of $400,000 for each Smith, but John and Jane find themselves under fire from an army of assassins. Fending off an attack which blows up their house, the Smiths steal their neighbor's minivan and successfully destroy three pursuing armored cars of attackers, all while bickering over their fighting styles and newly-discovered personal secrets.
After meeting with Eddie, the Smiths decide to fight together to preserve their marriage. They kidnap Danz from his high-security prison in order to give their employers something they want more than the Smiths. Danz reveals that he was merely bait, hired jointly by their employers after it was discovered that the Smiths were married, in the hopes of having one Smith kill the other. Danz also wears a cameo Fight Club t-shirt, referencing to Brad Pitt's previous movie of the same name.
John and Jane forgo their separate contingency plans and make their stand together. In the final fight scene of the film, the Smiths now working smoothly together as a team defeat an extended attack by a large number of armed forces during a long shoot-out inside a department store.
The film ends with the couple meeting the marriage counselor again, where the Smiths state how much their marriage has thrived and how happy they really are.