The 65,000-tonne behemoth set off from her home port to carry out the final phase of tests with the supersonic F-35B ahead of her maiden operational mission next year.
The latest set of trials comes just months after the first of the feared British fighter jets landed on Queen Elizabeth’s huge flight deck.
Previously, the £3.1bn leviathan has only carried out trials with the state-of-the-art warplanes while training off the east coast of America in 2018 and 2019.
The Royal Navy refused to say how long Queen Elizabeth will be at sea for or how long the flight trials are expected to take.
However, previous tests with the F-35s have lasted about five weeks.
Captain Angus Essenhigh, who took command of the future flagship earlier this month, said: ‘It is a real honour for me to be taking HMS Queen Elizabeth to sea for the first time as her new commanding officer.
‘This period at sea will build on the successes of the Westlant 19 deployment (to America), providing a fantastic opportunity for the ship to further its generation towards carrier strike, and will train and qualify UK F-35B pilots in UK waters for the very first time.’
The joint Royal Navy and Royal Air Force Lightning Force training squadron, 207 Squadron, will conduct the trials, flying aircraft to and from the decks, day and night from their base at RAF Marham.
Six pilots, both navy and air force, will carry out their aircraft carrier qualification in that time.
Tests will see pilots taking off and landing on Queen Elizabeth’s 4.5-acre deck in a range of conditions.
Lieutenant Commander Richard Turrell, flight deck officer on the supercarrier, said the tests were a ‘fantastic opportunity’ for pilots and sailors to work together.
‘My team are excited to get to sea and continue the development of our ship to air wing partnership throughout 2020 and beyond to deploying with full carrier strike capability in 2021,’ he added.
Hundreds of people lined Portsmouth’s Hot Walls to see off the ship, which had two Merlin Mk2 helicopters strapped to its flight deck.
Penelope Cooper, 58, and her husband Neil, 64, from Edinburgh, watched from the Round Tower.
Mrs Cooper said: ‘We saw her leaving Scotland and we’ve seen Prince of Wales while she was being built.
‘Both the ships are a huge deal in Scotland. We’re very proud of them. This is the first time we’ve seen Queen Elizabeth leaving Portsmouth. It’s great.’
The two Queen Elizabeth-class aircraft carriers are the biggest warships ever built for the Senior Service.
Both are based in Portsmouth and will have a 50-year lifespan. They’re also the only ships in the world purpose-built to operate the F-35 stealth jets.