The Q&A at an architecture convention in Orlando came days after her husband made his first public comments as ex-president at a Chicago university.
Mrs Obama, who left office with a 68% approval rating (10% more than her husband) said "politics is tough."
"It's all well and good until you start running, and then the knives come out."
It's hard on a family, she said. "I wouldn't ask my children to do this again because when you run for higher office, it's not just you. It's your whole family."
But "public service will always be in our blood", she added.
Although Mrs Obama had played down her political ambitions before, while first lady, this is the first time she has done so since the election campaign, when she was widely viewed as the most effective weapon in the Democratic armoury.
She did not openly discuss President Donald Trump by name during the 45-minute event, but she did make mention of "the new president" who marks his 100 days in office on Saturday.
"So far, so good," said Mrs Obama when asked about her own family's last 100 days, which included a yacht holiday near Tahiti.
She described how her dogs become confused by the sound of a doorbell, which is not a sound you hear at the White House. And now her two daughters can open their windows.
She also described fighting back tears when leaving the place where she had lived the longest in her entire life, saying: "I didn't want to have tears in my eyes because people would swear I was crying because of the new president."
Until this week, the Obamas had kept a low profile since the election, but they are each writing separate memoirs in a book deal worth $40m.
Mr Obama has drawn criticism from fellow Democrats over a $400,000 (£309,000) upcoming speaking engagement to a Wall Street investment firm.
Progressive senator Elizabeth Warren, who is seen as a possible 2020 presidential candidate, said she was "troubled" by Mr Obama's decision.
Senator Bernie Sanders, a 2016 Democratic presidential contender, said Mr Obama's speech was "distasteful", the Vermont Independent reports.