The film opens in Edinburgh. Narration by Angus the Hangman explains how the corpses of the hanged are transported to Dr Robert Knox for dissection. Knox's rival, Dr Alexander Monro, wants the steady supply of cadavers but is forced to rely on severed limbs for dissection. Monro's assistant Charles Darwin arrives with a letter containing a bylaw directing that all corpses thenceforth must be sent to Monro. Angus tells Knox's assistant, Patterson, the news. Patterson delivers the message to Knox.
William Burke and William Hare, immigrants from Ulster, attempt to sell cheese mould as a patent medicine. When their fraud is discovered, they flee to an inn owned by Hare's wife, Lucky. She tells them that one of the lodgers has died. Burke and Hare have to move the body, on the way they stop for a drink and Hare hears from Fergus, a local henchman of villain Danny McTavish, that Dr Knox pays for cadavers, especially now demand has gone up. Burke and Hare decide to sell the corpse to Knox. They are forced to break the corpse's spine to fit it into a barrel in order to smuggle it through the city. Burke and Hare present the now-mangled corpse to Knox. After some negotiation, Knox agrees to pay them a good sum of money for each corpse they bring him for dissection. In addition to using cadavers in lectures, Knox is attempting to create a pictorial reference of the human body by using an early form of photography, using this he hopes to win royal patronage from the king when he comes to Holyrood Palace.
Burke and Hare try grave-digging to procure more cadavers, but fail (by digging up a long buried skeleton), then they run off chased by the militia, Burke gets shot in the rear. Getting back to the inn they find Lucky drunk and barely conscious. Lucky says she is drinking because Joseph, another lodger at the inn, is near death. Not willing to wait for the outcome, Burke and Hare suffocate Joseph and take the body to Knox. Flushed with money Burke and Hare dress up for a night in a posher pub. There they meet a young former prostitute, Ginny Hawkins, who loudly performs an excerpt from Macbeth. The patrons ignore her. Burke falls in love at first sight and asks her why she did this, and she says that it is her ambition to become an actress. Burke plans to use his money to finance Ginny's theatrical ambitions, and Hare decides to open a funeral parlour.
Hare comes home to find Lucky has cooked for him and is in good spirits, he is suspicious, then scared when Lucky tells him she knows what he and Burke have been up to, but surprisingly she thinks it's a good idea and makes Hare give her a pound per corpse, as a tax between man and wife.
Burke is kidnapped and bundled into a horse carriage by McTavish and Fergus, who have already captured Hare. McTavish threatens to kill them unless they give him half the money from Knox. Forced to agree, they are then thrown from the carriage. As they trek back to the inn, they plan a string of murders to make up their losses to McTavish. The people of Edinburgh becomes suspicious of all the deaths in the area as does Police Captain Tom McLintock of the militia. Missing posters of the dead are put up and Burke begins to panic, Hare says they have finished the murders and will go into the funeral parlour business.
McTavish kidnaps Hare again and attempts to extort the remainder of the money. Shortly afterward, McTavish appears as Knox's next dissection cadaver, he is recognised and McLintock takes notice. He investigates Dr Knox and discovers 'photographs' of all the missing people dead and dissected, Knox tells McLintock about Burke and Hare. McLintock arrests Burke and Ginny, and Hare and Lucky, while both couples are having sex. In prison Burke is repentant but Hare tells him not to confess or all of them, including the women will be hung. Meanwhile the solicitor general and the lord provost want to keep the scandal out of the headlines- it would have ruined the reputation of Edinburgh's medical schools, and the money they generated. They gently coerce McLintock into a deal by making him a colonel, they then burn the photographs. McLintock tells the prisoners that if any one of them confesses to the murders, the others will go free. Burke agrees to confess if he and Ginny can finish what they were doing when McLintock apprehended them.
Just before Burke's hanging, Angus advises him to speak if he has any final words. Burke sees Ginny in the crowd, and says, "I did it for love."
Onscreen text over the credits describes the fates of all the characters in the story, concluding with an image of the actual skeleton of William Burke at the Anatomical Museum of the University of Edinburgh Medical School.
Burke & Hare was developed by Ealing Studios, who had been known for producing acclaimed black comedy films such as Kind Hearts and Coronets and The Ladykillers. John Landis read the screenplay, which piqued his interest in making the film. Landis wanted the film to be similar in style to Ealing's black comedies, as well as to the films of Laurel and Hardy, describing the portrayal of Burke and Hare in this film as an "evil Laurel and Hardy".
David Tennant was originally cast in the role of William Hare, but left the production before principal photography began; he was replaced by Andy Serkis.
Many cast members of the sitcom Spaced appear, including Simon Pegg, Jessica Hynes, Bill Bailey, Reece Shearsmith and Michael Smiley.
Three actors from the John Landis film An American Werewolf In London appear: Jenny Agutter, David Schofield and John Woodvine.
Filming took place around Edinburgh with some scenes also being shot in Stirling, London and at Knole in Kent, and also at Ealing Studios. The script was written by Piers Ashworth and Nick Moorcroft, who previously wrote St. Trinian's, also for Ealing, which was the highest grossing British independent film of the last 10 years.
The first official trailer for the film was released on 5 October 2010. It was shown in some UK cinemas before Paranormal Activity 2.
It was released on 29 October 2010.
Rotten Tomatoes, a review aggregator, reports that 33% of 55 surveyed critics gave the film a positive review; the average rating was 4.8/10. Metacritic rated it 46/100 based on 10 reviews. Nathan Rabin of The A.V. Club rated it B and called it a "minor but welcome return" for Landis. Neil Genzlinger of The New York Times described it as "a ghoulish comedy" not for nitpickers. Charles Gant of Variety called it an "amiable, creaky comedy" that represents "a step back from the brink." Ray Bennett of The Hollywood Reporter wrote that it is "unpleasant drivel that tries to make fun out of murder."