NOTE: This spoiler was submitted by Jeremy
Lord Charlie Mortdecai (Johnny Depp) is an eccentric art dealer with a curly mustache. He is at a casino in Hong Kong meeting with a gangster named Fang (Junix Inocian) to sell a rare vase. Mortdecai is about to collect the money when Fang reminds him that during their last transaction, Mortedcai sold him a piece of art for $3 million when it was only worth $1 million. As payback, Fang wants to collect one of Mortdecai's fingers. One of Fang's men tries to do the job when Mortdecai's faithful manservant/thug Jock (Paul Bettany) steps in and beats the goon. A shootout ensues, forcing Mortdecai and Jock to flee.
Recently, Mortedcai and his wife Johanna (Gwyneth Paltrow) have come into debt. After returning to his home in London, Johanna sees the mustache her husband has grown and she is utterly repulsed by it, gagging whenever he kisses her (and making him gag in response as he has a sympathetic gag reflex). She ponders what they will do about their financial concerns. Here, we learn how much Mortedcai loves his wife, and he also mentions a bit about Jock, specifically how much sex he has and how it's gotten him in hot water (i.e., sleeping with a farmer's daughter).
A woman named Bronwen (Norma Atallah) is working on a painting from the artist Goya when she is shot in the back with an arrow. After Bronwen expires, a thief swipes the painting and leaves her home, when he is knocked out by yet another thief.
Inspector Alistair Martland (Ewan McGregor) is put on the investigation to recover the painting. He visits Mortdecai to ask for his services. Martland has been in love with Johanna since their college years, and he harbors a slight vendetta against Mortdecai after catching them sleeping together. He informs Mortdecai and Johanna of the theft, with their prime suspect being a criminal named Emil Strago (Jonny Pasvolsky), and he convinces Mortedcai to recover the painting with Jock, to which they agree on the condition of receiving 10% in payment after they plan on selling the painting to an American dealer by the name of Milton Krampf.
Mortdecai first visits an art aficionado named Sir Graham (Michael Culkin) to get a clue as to where the painting may be. Then he visits an art smuggler named Spinoza (Paul Whitehouse) in a garage. Spinoza has apparently also been screwed over by Mortdecai in the past, as he angrily yells and swears at the man. Emil shows up and shoots at the men. Spinoza is killed, while Mortdecai and Jock take one of the cars and drive away.
While her husband is away, Johanna does a bit of investigating on her own.
She meets with a man known as The Duke (Michael Byrne), who informs her that the painting was taken by a friend of his from the war. It supposedly has codes written on the back that lead to the location of a hidden stash of Nazi gold.
Mortdecai learns that the painting was stashed in the car that he was riding. A while later, he is kidnapped by Russian thugs working for a man named Romanov (Ulrich Thomsen). They want their hands on the painting too, and they threaten to electrocute Mortdecai's balls until the man pushes one of the thugs out the window along with himself to escape with Jock. After returning to London, Martland forces Mortdecai to go on ahead to America to meet with Milton Krampf.
Mortdecai and Jock arrive in Los Angeles where the former meets Krampf (Jeff Goldblum) and his apparently nymphomaniac daughter Georgina (Olivia Munn). The painting has been selected for a gallery to be on display for a party later on. Jock proposes that they sneak into the room where it's being kept and swipe the painting for themselves when nobody is looking. Mortdecai also gets in touch with Johanna and overhears Martland in the room with her, thinking she is unfaithful. He tries to convince her he is staying in a brothel out of spite.
On the night of the party, Mortdecai is nearly seduced by Georgina, until he is caught dancing with her (and with his hand on her breast) by Johanna, who has also shown up with Martland. Mortdecai leaves and goes to take the painting with Jock.
They find Krampf has been murdered by Emil, who has nabbed the painting. Martland and Johanna come in with Martland aiming a gun at Emil. However, it turns out Georgina is in cahoots with Emil, and they are also lovers. They take the painting and run for it, with the other four chasing after them. The villains go to a motel and try to find the codes with lighter fluid and a blowtorch. In the chaos, Emil spills the fluid and ignites it with the torch near a conveniently placed pile of petrol. Everybody runs as the motel room explodes, destroying the painting with it.
Johanna informs Mortdecai that this painting was a fake. The real one is with The Duke, which he actually did tell her when he invited to show it to Johanna in the bathroom (she thought he was talking about showing her his penis). The couple return to London to find The Duke, only to learn that he has passed away. His widow does allow them to go to the bathroom and find the painting.
The couple puts the painting up for an auction later that evening, hidden as a fake under a familiar painting owned by Mortdecai. Fang is informed of this and goes down to collect Mortdecai's finger. Romanov and his goons also show up to the auction with Sir Graham. Mortdecai and Jock subdue Romanov's goons before encountering Fang's goons. Those two nearly take one of Jock's fingers instead, until Mortdecai takes a club and beats them down to save his friend. Mortdecai runs to the auction, where Emil has been seated next to Johanna with a knife. Mortdecai arrives and makes a high bid until Romanov outbids him. The painting is sold to him, giving Johanna a moment to pepper-spray Emil in the face, and he is apprehended by Martland.
We learn that Romanov purchased the wrong fake, and he decides to have Sir Graham's balls. Martland accepts that he will never be with Johanna, and he leaves her be. Mortdecai has collected some money, but the rest is paid off for taxes he skipped.
In the end, Mortdecai and Johanna continue to love each other and remain faithful through thick and thin. He agrees to finally shave his mustache if it will make her happy, because he would do anything for her. Johanna decides to let it stay. She kisses him passionately, until moments later when she gags, forcing Mortdecai to follow suit.