Construction executive John (Brad Pitt) and tech support consultant Jane (Angelina Jolie) are answering questions during marriage counselling. The couple has been married for "five or six" years, but their marriage is suffering to the point that they cannot remember the last time they had sex. They tell the story of their first meeting in Bogotá, Colombia, where they were both secretly on the run from the Colombian authorities. Since the authorities were looking for tourists travelling alone after a recent assassination, the two claimed to be together to avoid being questioned. They quickly fall in love and get married. John later states that Jane "looked like Christmas morning" to him on the day they met; she thought he looked like "the most beautiful 'mark'" she had ever seen.
In reality, John and Jane are both skilled field operatives working for different contract killing firms, both among the best in their field, each concealing their true professions from one another. The couple live in a large Colonial Revival house in the suburbs, and to keep up appearances, reluctantly socialize with their "conventionally" wealthy neighbors. 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 DIA prisoner Benjamin "the Tank" Danz (Adam Brody) during a transfer, they encounter each other on the job and the hit ends up botched: Danz survives, while John and Jane are assigned to kill each other instead.
After making escalating attempts on each other's lives, the Smiths' conflict culminates in a massive shootout that nearly demolishes their home. In a protracted, evenly matched fight, they wind up with guns in each other's faces. John declines to shoot, his feelings for Jane rekindled, and lays his gun down. Jane finds she cannot shoot John either, and the two have passionate (and almost violent) sex.
The renewed Smith partnership is quickly threatened by their employers, who join forces to eliminate the couple. John's best friend and co-worker, Eddie (Vince Vaughn), turns down a bounty of $400,000, but John and Jane find themselves under fire from an army of assassins. Fending off an attack which blows up their pockmarked house, the Smiths steal their neighbor's minivan and successfully destroy their attackers' three pursuing armored sedans, 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 to use him as a bargaining chip. 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. John and Jane forgo their separate contingency plans and make their last stand together, fending off an assault of heavily armed operatives inside a home decorating store.
The film ends with the couple meeting the marriage counselor (William Fichtner) again, where the Smiths state how much their marriage has thrived, with John encouraging him to ask for an update on their sex lives (to which he silently answers "10/10"). An alternative ending shows that they chose to move to Rome and had a child who inherited their assassin skills.
Brad Pitt as John Smith
Angelina Jolie as Jane Smith
Vince Vaughn as Eddie
Adam Brody as Benjamin "the Tank" Danz
Kerry Washington as Jasmine
Keith David as Father
Chris Weitz as Martin Coleman
Rachael Huntley as Suzy Coleman
Michelle Monaghan as Gwen
Stephanie March as Julie
Jennifer Morrison as Jade
Perrey Reeves as Jessie
William Fichtner as Dr. Wexler, the marriage counselor (uncredited)
Angela Bassett as the voice of Mr. Smith's boss (uncredited)