Hawking, who has motor neurone disease and has been paralysed for most of his life, will make a rare public appearance to narrate segments of the ceremony, which is due to start at London's Olympic Stadium at 1930 GMT.
The curtain-raiser to 11 days of sport, involving the traditional parade of many of the record 4 200 athletes taking part, will begin with a fly-past by Aerobility, a charity which helps disabled people become pilots.
But Hawking, who speaks using a voice synthesiser, will take centre-stage to deliver a series of messages to the 80 000-strong crowd and millions watching on television around the world.
"Everyone knows about Professor Hawking and his extraordinary theoretical work and extraordinary writings which have made very complex ideas about science accessible," co-artistic director Bradley Hemmings told a news conference.
"What came through to us was the humanity and humour of Professor Hawking. He's a fun guy."
The show – which features more than 3 000 performers, many of them with disabilities – will also see Queen Elizabeth II officially open the Games.
Hawking's involvement fits into the "Enlightenment" theme of the opening ceremony, said co-director Jenny Sealey, who like Hemmings is a theatre director with a long history of working with disabled performers.
Sealey – who is profoundly deaf and used a sign language interpreter at the news conference – described Hawking, the author of the bestseller A Brief History of Time, as "the most famous disabled person anywhere in the world".
Through him, the crowd "will be taken on the most exquisite journey of discovery, inspired by the wonder of science", starting at the 18th century "Enlightenment" to the modern era, she added.
Hemmings said Hawking would speak about "the origins of the universe and how humanity has tried to understand how everything is ordered, and how things came to be".
He added: "[He] makes the point that even if there was a universal theory of everything, even if we understand the mechanics, what breathes life into these equations, what makes it worth understanding is humanity."
Sealey said the Enlightenment was a "period of time of phenomenal change intellectually, philosophically, culturally and socially" and disseminating knowledge.
The Paralympics were "absolutely fundamental to that vision", she said, adding: "If we think about transforming perceptions, the Paralympics do that".
The executive producer for all four Olympic and Paralympic opening and closing ceremonies, Stephen Daldry, described the Paralympic opening as "the most extraordinary piece of work".
"What we are going to get from Jenny and Bradley is something very unique and very different, much more classically driven" than Danny Boyle's opening Olympic celebration of British history and pop culture and Kim Gavin's musical closing.
Like Boyle, Sealey and Hemmings have been inspired by William Shakespeare's The Tempest to create a storyline aimed at promoting ideas of empowerment and inclusion through a central character, Miranda.
Hawking and veteran actor Ian McKellen, who plays a Prospero figure, talk about "finding out what it is to be human", said Sealey.
"Don't just look down at your feet, look at the stars. Be curious because if you're not curious, you might as well just give up," she added.
Daldry, a film director who was Oscar-nominated for the 2000 film Billy Elliot, added: "It's about challenging our perceptions in a very different way from the other ceremonies … It's a radical show." – Sapa-AFP