The airport is on track to open in late 2026, and the two airlines were the first to sign up to offer flights.
Qantas chief executive Alan Joyce said 15 aircraft would initially operate from the airport.
The planes are expected to carry about four million passengers through Western Sydney airport per year, on more than 25,000 flights.
Popular domestic routes to Melbourne, Brisbane and the Gold Coast will be running within the first year of the airport opening.
Mr Joyce said the airlines were in talks with the airport to expand their offerings to international flights.
"It's absolutely breathtaking that in just over three years, we're going to have Qantas and Jetstar aircraft rushing down this roadway," he told reporters on Thursday.
"I have absolutely no doubt this will be the biggest airport on the Qantas network one day."
The agreement is expected to generate about 700 operational jobs, which the airlines will recruit locally to fill.
Prime Minister Anthony Albanese accompanied Mr Joyce on a tour of the airport construction site, which is now more than halfway finished.
Mr Albanese said the economic activity generated by the new airport would shift Sydney's focus to the west.
"What we can see is a vision becoming a reality before our very eyes," he said.
"Western Sydney International Airport will change the dynamic of Sydney.
"This will be top of the range from day one, which will make an enormous difference.
"It will make a difference for people in Western Sydney, and I'm very pleased that Qantas is making this announcement today."
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