The Ocean's Eleven stars will premiere '50s-set crime comedy Suburbicon at the event, which Damon stars in and Clooney co-writes and directs.
Damon will also be seen in festival opener Downsizing, directed by Alexander Payne.
After premiering three major Academy Award winners in a row, Venice is seen as a good luck charm for the Oscars.
Previous films to debut at the event include Birdman and Spotlight, which went on to win the Academy Award for best picture.
Last year's opener La La Land was also named best picture - but only as the result of an envelope mix-up.
In Suburbicon, Damon character tries to understand the dark mysteries of his seemingly peaceful town along with wife Margaret, played by Julianne Moore.
In Downsizing, which also stars Kristen Wiig, Neil Patrick Harris and Jason Sudeikis, he plays a man who literally shrinks himself in search of a better life.
Guillermo Del Toro will debut his other-worldly fairy-tale The Shape of Water. Set against the backdrop of America's Cold War era, it stars Sally Hawkins, Michael Shannon and Octavia Spencer.
Darren Aronofsky will also premiere his latest film Mother!, starring Jennifer Lawrence and Javier Bardem.
The director said he was "excited" to be unveiling the horror film, which will also screen at Toronto.
Chinese contemporary artist and activist Ai Weiwei will also be competing in the festival with his film Human Flow, a film about the global refugee crisis.
Spanning 23 countries over the course of a year, the film focuses on both the scale of the crisis and its personal human impact.
Weiwei said: "There is no refugee crisis, only a human crisis. The border is not at Lesbos, but really it is in our hearts and minds."
Jane Fonda and Robert Redford will be celebrated with the Golden Lion lifetime achievement award at the festival.
Netflix film Our Souls at Night, in which they both star, will be premiered out of competition.
Alberto Barbera, the festival's artistic director, called Fonda "one of the great protagonists of contemporary international cinema" and Redford "a thoughtful, instinctive actor with a keen sense of detail."
New to this year's festivities is Venice Virtual Reality, billed as the first competition for VR works at a major film festival.
The 74th edition of the Venice Film Festival runs from 30 August to 5 September.
Follow us on Facebook, on Twitter @BBCNewsEnts, or on Instagram at bbcnewsents. If you have a story suggestion email entertainment.news@bbc.co.uk.
George Clooney and Matt Damon are set to bring some Hollywood glitz to this year's Venice Film Festival.