The non-stop journey stands in stark contrast to the original flights by Australia's national carrier to the UK.
Leaving Sydney, it stopped in Darwin in northern Australia, Singapore, Calcutta in India, Karachi in Pakistan, Cairo in Egypt, Tripoli in Libya and, finally, London.
This new route is around three hours shorter than the previous fastest route available to passengers, with the plane no longer having to stop and refuel in the Middle East.
Qantas said it is able to reduce the time of the 9,000 mile (14,498km) flight by eliminating stopovers and picking paths based on the best winds for efficiency and speed.
The former champion, Singapore Airlines' 15,300km Singapore-New York route, was discontinued in 2013.
The return flight QF10 will depart Heathrow for Perth at 13:30 local time today.
To succeed, the route must defy the boom-and-bust commodities cycle that has preyed on Western Australia.
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The number of ultra-long haul flights - those over 7,000 nautical miles (12,964 kilometres) - has almost tripled to 19 over the last decade, according to travel data provider OAG, as smaller, fuel-efficient twin-engine planes like Boeing Co's 787 and Airbus SE's A350 have entered service.
The route will be operated with the newest aircraft recently ordered by Qantas, the Boeing 787-9 Dreamliner.
Tourism WA chairman Nathan Harding said the organisation would work with Qantas to develop at least one more direct route, likely Frankfurt or Paris, within the next few years.
Singapore Airlines Ltd expects to revive the world's longest non-stop commercial flight, from Singapore to NY, in the second half of this year after a five-year hiatus due to the new aircraft technology and lower fuel prices.
Convenience is also expected to be a drawcard, given passengers fly to Perth then embark on their long-haul journey from the same airport.
Qantas CEO Alan Joyce with chefs at the new Qantas lounge before the first direct flight to Heathrow airport from Perth.
The flight, dubbed QF9, will run daily.
"It's not that far away and the opportunity for all of us in that is quite massive", he said.