The former Oasis star and his band will close the first night of the iconic music extravaganza at Seaclose Park in Newport on Friday, June 14, for their first performance since 2012.
George will head up the main stage on the Saturday night, and is ''flattered'' to have been promoted to headliner.
The 'Shotgun' hitmaker said: ''It's been less than 18 months since I was last at The Isle of Wight Festival, but it already seems like a world away.
''In the time since, my second album 'Staying At Tamara's' has been released and I've taken these songs around the world and back.
''It's going to be brilliant to return to the beautiful Isle and play those new songs to an audience that has now heard the record.
''I'm extremely flattered to have been asked to headline and can't wait to get up and play. See you soon!''
Whilst Simon Neil and co, who will close the festival on Sunday, June 16, commented: ''We are delighted to be headlining The Isle of Wight Festival again. 'Tis a beauty. Hail Satan!!''
Joining the three main headliners is Fatboy Slim, who will make his debut at the festival, and has the job of entertaining the crowds until the early hours with his DJ set after George's performance on June 15.
Former Verve frontman Richard Ashcroft, Lily Allen, Anne-Marie, Bastille, Courteeners, Madness, Miles Kane, Mystery Jets and Rick Astley are also set to play across the three main days.
Plus Jess Glynne and Jax Jones will be providing pop bangers.
Rising stars, including this year's BRITs Critics' Choice winner Sam Fender, Australian rockers DMA'S, singer/songwriter Freya Ridings, indie stars IDLES, 'Sucker Punch' hitmaker Sigrid and 'Leave a Light On' singer Tom Walker also feature on the jam-packed bill.
This year sees the return of the Haçienda Classiçal, curated by DJ Graeme Park, Executive Producer Peter Hook (Joy Division, New Order) and Musical Director Tim Crooks, at the Big Top.
A perfect fit, with Manchester's very own Noel Gallagher headlining this year, their show features their own interpretations of the seminal music that blasted the halls of the iconic Haçienda nightclub - which was frequented by former Oasis stars Noel and Liam Gallagher, Richard Ashcroft and many others, and was co-funded by new wave stars New Order - in the 80s and early 90s.
They will be joined on stage by the Manchester Camerata orchestra.
Graeme said: ''I can't wait to return to The Isle Of Wight Festival with Haçienda Classical. Last year was absolutely amazing and I'm really excited to be returning again this year with our brand new 2019 show. This is going to be incredible!''
Tickets for The Isle of Wight Festival 2019 go on sale on Friday (25.01.19) at 9am from www.isleofwightfestival.com
American Thighs was released on this day in 1994.