Yvonne Kershaw, a 64-year-old grandmother from Petworth in West Sussex, landed the Virgin Atlantic flight from Cancun in Mexico.
Mrs Kershaw joined the airline in 1990 and was granted command of the Boeing 747 aircraft three years later.
She said it had taken passengers a few years to get used to seeing a woman coming out of the flight deck.
"I suppose normally they would expect to see a silver-haired fox flying the aeroplane in command," she added.
"Breaking down those barriers wasn't easy but nobody ever said it would be.
"What you need is passion about your job, determination and skill."
Mrs Kershaw learned to fly at the age of 19 and after flying small aircraft around Europe and north Africa she gained her commercial pilot's licence and flew executive jets.
When she joined Virgin Atlantic its fleet included only four 747s.
"It's such an iconic aeroplane and it's what I wanted to fly. For decades it was the largest aircraft in the world and the most loved by everybody," she said.
Mrs Kershaw has captained more than 2,000 flights with more than 18,000 flying hours in the jumbos.
She said she was "slightly tearful" after landing her final flight and would miss the role "enormously".
"With long-haul it's not a job, it's a way of life, because you spend so much time away from home with crew. They become part of your extended family."
The UK's first woman jumbo jet pilot has retired after landing at Gatwick Airport for the last time.