Voiced by the show's creator Seth MacFarlane, Brian had been a key part of past storylines and gags. Best friend and baby genius Stewie tried in vain to go back in time and save him but was unable to after disassembling his time machine.
Fans were so shocked by the death that an online petition has been launched to 'Bring back Brian'.
Executive producer Steve Callaghan has explained that the idea came about after it "sort of caught fire in the writers' room".
"We thought it could be a fun way to shake things up and got very excited about the way this change will affect the family dynamics and the characters," he told E!.
"As much as we love Brian, and as much as everyone loves their pets, we felt it would be more traumatic to lose one of the kids, rather than the family pet."
Brian had been in the family since the pilot episode, eleven seasons ago in January 1999. His death left a void that the team decided "needed to be filled both comically and also for the interpersonal relationships between the characters".
To solve the dilemma, MacFarlane rapidly wrote in a new dog, Vinny, voiced by Tony Sirico from The Sopranos.
"Seth thought it would be fun to write a character based around [Tony's] voice and his personality and just who he is as an actor," Callaghan said.
"Brian was very smart and studious and intellectual, and Vinny is just a lot more rough around the edges."
But it was the speed at which Brian was replaced that has angered viewers the most. Fans of the show took to Twitter to share their upset and sense of injustice at their favourite dog's untimely demise.
I can't believe Family Guy killed off Brian. Stewie's reaction had me sobbing. I've never felt so upset at a cartoon before.— James (@Jamesgoodall4L) November 25, 2013
The series may have gone downhill but goddammit you don't write Brian out of Family Guy. That is not cool MacFarlane.— Jake Rosenthal (@ScouseyDragon) November 25, 2013
The producers have said they are confident Family Guy fans will move on from Brian's death in time and warm to new pet Vinny.
"Our fans are smart enough and have been loyal to our show for long enough to know that they can trust us," said Callaghan. "We always make choices that work to the greatest benefit of the series."
Rumours that Brian will be resurrected in a future episode have been circulating by hopeful fans while others have vowed never to watch the show again.