The valuable 90-centimetre (three-foot) long continental giant rabbit had previously been described as "fit as a fiddle", and his death in the cargo section of a Boeing 767 comes as a mystery.
"Something very strange has happened and I want to know what," breeder Annette Edwards, from Worcestershire in central England, told British newspaper The Sun.
"Simon had a vet's check-up three hours before the flight and was fit as a fiddle," she said, adding: "I've sent rabbits all around the world and nothing like this has happened before."
Edwards also revealed that "the client who bought Simon is very famous. He's upset".
Ten-month-old Simon was expected to grow to become the world's biggest rabbit, after his father Darius grew to 1.32 metres, Edwards said.
According to the breeder such rabbits cost £5,000 ($8600AUD) a year to keep.
The incident comes less than three weeks after United Airlines drew global outrage for forcefully dragging a passenger off an overbooked flight.
Footage of the April 9 incident captured by fellow passengers went viral on social media.
It also caused a public relations calamity for United and airport officials, sparked worldwide outrage, and led to multiple apologies from United as well as an internal probe of its policies and practices.
United Airlines said it was "saddened" to hear the news of Simon's death.
"The safety and well-being of all the animals that travel with us is of the utmost importance to United Airlines and our PetSafe team," it said.
"We have been in contact with our customer and have offered assistance. We are reviewing this matter."
Figures from the US Department of Transportation show that 35 animals died in air transit in 2015, across the country's 17 main carriers.
United Airlines account for nine of those deaths, the highest of all the carriers. It transported over 97,000 animals during that year.
