They were originally bred for rescue work by the Great St Bernard Hospice, a traveler's hospice on the often treacherous Great St Bernard Pass in the Western Alps, between Switzerland and Italy. The hospice, built by and named after Italian monk Bernard of Menthon, acquired its first dogs between 1660 and 1670.

St. Bernards are often portrayed, especially in old live action comedies and classic cartoons, wearing small barrels of brandy around their necks. Avalanche victims supposedly drank the brandy to stay warm while awaiting rescue. The monks of St. Bernard deny that their dogs ever carried wine or brandy, though some were trained to bring milk from cowsheds. They attribute this misconception to an 1820 painting by Charles Landseer called Alpine Mastiffs Reanimating a Distressed Traveller.

A St. Bernard named Benedictine holds the world record for the Heaviest Dog Ever. Benedictine, who displaced an English Mastiff named Zorba as the heaviest dog of all time, reportedly weighed 357 pounds.

The most famous St. Bernard to save people at the pass was Barry der Menschenretter ("Barry the people rescuer") who reportedly saved somewhere between 40 and 100 lives. There is a monument to Barry in the Cimetiére des Chiens, and his body was preserved in the Natural History Museum in Bern.

The classic St. Bernard looked very different from the St. Bernard of today because of crossbreeding. Severe winters from 1816 to 1818 led to increased numbers of avalanches, killing many of the dogs used for breeding while they were performing rescues. In an attempt to preserve the breed and give them a thicker winter coat, the remaining St. Bernards were crossed with Newfoundlands brought from the Colony of Newfoundland in the 1850s, but the plan backfired and they lost much of their use as rescue dogs in the snowy climate of the Alps because the long fur they inherited would freeze and weigh them down.

The 1992 comedy film Beethoven features a friendly but troublesome 200-pound (90 kg) longhaired St. Bernard and, in later sequels, his mate and their brood of unruly pups. According to the producers of the sequel Beethoven's 2nd, the St. Bernards used in the film grew so fast during filming that over 100 St. Bernard puppies were cast to portray the sequel's four puppies (Tchaikovsky, Chubby, Dolly, and Mo).

Big jowls lead to big drools. It's just the way their anatomy works.

The longest tongue on a dog measures 18.58 cm (7.31 in) and belongs to Mochi, a female St. Bernard who was measured in Sioux Falls, South Dakota, USA, on 25 August 2016. Mochi was rescued by the Rickert family when she was two years old. "We love her unconditionally despite that crazy, long tongue that causes people to stare and laugh," said her owner Carla Rickert.

The average lifespan of the St. Bernard dog is 8-10 years, with around one in five dogs living past 10 and the oldest recorded St. Bernard in the UK living to almost 13.

Theodore Roosevelt kept the White House hopping from 1901 to 1909 with many animals, including dogs, cats, ponies, snakes, birds, rabbits, guinea pigs, and even a laughing hyena. But according to the Associated Press, Roosevelt's "most interesting pet" was Rollo, a massive St. Bernard who enjoyed bounding after the President's children on the White House lawn. Astonished guests expected the big dog to pounce on the children and devour them, but Rollo never uttered a growl of protest or bared his teeth when the children played rough games with him.