Dozens gathered at Sydney Airport on Wednesday to wave goodbye to QF7474, writing messages on the plane's body and reading tributes.
The impact of the virus on travel means the 747 and others were retired by Qantas six months earlier than planned.
It will sit in the US Mojave Desert.
"It's hard to overstate the impact that the 747 had on aviation and a country as far away as Australia," said CEO Alan Joyce.
"This aircraft was well ahead of its time and extremely capable. [It] put international travel within reach of the average Australian and people jumped at the opportunity."
Last month Qantas said it would axe 6,000 jobs as part of its plans to survive the coronavirus pandemic.
Around 150 people gathered to say goodbye to the plane, which was also given a water cannon salute. Originally, thousands were expected for a farewell planned for the end of the year.
The Qantas 747 fleet has carried more than 250 million people in almost half a century of service, including Queen Elizabeth II and every Australian Olympic team since 1984, said a Reuters report.
Qantas has grounded most of its international flights until at least July 2021 due to the lack of international travel demand.
Last week, British Airways announced that it would also retire all of its Boeing 747s, adding that it would operate more flights on more fuel-efficient planes such as the new Airbus A350s and Boeing 787 Dreamliners.