The enormous eight-storey painting will tower over residents and visitors near Union Square in the heart of the city’s downtown.
The artist behind the mural, Argentine Andres Iglesias – known as Cobre – said he hoped it would impress on those who saw it the necessity of taking action against climate change.
“Climate change is real. This girl Greta is awesome and she knows what she’s doing,” he told the local news website SFGate.
“I hope with this mural people will realise we have to take care of the world.”
He is donating his time for free to the project, which is being funded by a local environmental charity.
Paul Scott, the director of the non-profit One Atmosphere, said he hoped the Greta Thunberg artwork would be the first of many depicting climate change activists across San Francisco.
“Greta is having profound effects on the environmental movement right now,” Mr Scott also told SFGate.
“We’re hoping [the mural] is going to touch people and that it will open up their hearts and minds to the unbridled conviction of Greta’s message.
“She is a bright light in a dark time and we hope people will follow her lead and make some changes.”
Ms Thunberg, who first became famous for leading the school strike for climate movement in her native Sweden, recently visited the United States for the UN’s General Assembly, which raised her profile even higher.
There, she railed against world leaders, accusing them of stealing her “dreams and her childhood” with their “empty words”.
“People are suffering. People are dying. And all you can talk about is money and fairy tales of eternal economic growth. How dare you.”
Famously, Ms Thunberg travelled by boat across the Atlantic to visit the UN in New York, as she refuses to fly.
Earlier this year, the 16-year-old was immortalised in another mural in Bristol, which showed her partially submerged by rising glacial sea levels.
Previous studies have suggested climate change will particularly devastate San Francisco, as the low-lying Bay Area becomes more susceptible to flooding.
The recent spate of deadly wildfires have also concentrated policymakers’ thoughts in California, as scientists say they are exacerbated by climate change.