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At an appearance this morning at the company's loft headquarters in the South of Market district, Newsom said he had recently signed up for the service, which allows members to make short, public postings about their daily activities via email or text message.
"Hey, I got a Twitter account," Newsom recounted telling his staff.
"Everyone panicked," he said.
Since then, Newsom said, more than 40,000 people have linked up with his account, responding to his posts with "solicited and unsolicited" advice on everything from spelling mistakes to suggested baby names for his first child.
Newsom said he tries to answer some of the queries, including advising one man complaining about a pothole in his neighborhood that he'd ordered the city to take care of it.
"The best part about it is, no one believes it's actually me responding to these, but it is," he said.
"A lot of these, when I tweet back, people are, 'Don't you have something better to do?'" he said, smiling.
But Newsom's appearance, with Twitter CEO Evan Williams and co-founder Biz Stone, also had a more serious and constructive tone about the future of technology in government and business growth in San Francisco, a city saddled with a huge budget deficit in a struggling economy.
"The Bay Area obviously attracts the best and the brightest in terms of our field...technology and the Internet," said Williams.
"We feel like we're just scratching the surface," Williams said of his company's plans for the future.
The 2006 startup now has about 30 employees, and plans to double its staff this year, Williams said.
"Thank you for not leaving our city as you grow," Newsom told Williams and Stone.
Using Twitter as an example, Newsom said he wants to keep San Francisco as a place to recruit top talent in biotech and life sciences, digital media and arts, and green technology, and to keep those industries in the city.
"A sort of Silicon Valley North," he said.
Newsom also said he believed government could use services like Twitter to help release information to the public.
"This is going to become an incredibly valuable tool for us," Newsom said.
According to Williams, Twitter has become a source for real-time information to be distributed on public events, protests, transit delays and emergencies such as fires and earthquakes.
"It's on Twitter faster than it is anywhere else," he said.
Williams said he believed it makes the community more informed, connected and efficient.
"Twitter is more about the triumph of humanity than technology," Stone added.
In addition to an active Twitter account for San Francisco's main city government site, at least one city department has also followed Newsom's lead.
Last week, the city's Water Department signed up a Twitter account, and according to spokesman Tony Winnicker, it will be used to inform the public of emergencies such as water main breaks, storms and flooding, and water usage information.
The messages will be useful and the department will not "bombard people with too many," said Winnicker.
"They're short, timely, relevant bursts of information, which in case of emergency...it's ideal," he said.
"It's essentially a step toward real-time customer service," Winnicker said. "It's another step toward making public agencies more accountable."
On a political level, Newsom said he has used Twitter to discover what people are paying attention to, including "what people picked up on in a speech."
"Talk about democratizing information," he said. "I mean, you can't run a public opinion poll like that."
Even as today's meeting -- broadcast live on the city's Web site -- was about to wrap up, Newsom said he'd just received a Twitter response from the pothole complainant he had mentioned several minutes earlier.
The man "just tweeted us back," said Newsom, "with another one."
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