She says everyone needs to take the virus seriously as people get together this weekend.
Lightfoot says there's been a big surge in cases, and Chicago will reach the "high" level of cases either this week or next week.
She says 47 Illinois counties are already there, and so is New York City and Los Angeles.
The mayor says when the "high" level is reached, she’ll be asking all city residents to mask up again.
"If and when Chicago and Cook County reach that level, we will issue a mask advisory. Let me just underscore that: a mask advisory. And what that means is we will be asking all Chicagoans age two and older to wear masks in indoor, public settings," Lightfoot said.
The city is working on new signs for businesses and public spaces.
The advisory is a request, rather than a mandate, that anyone age 2 and older wear a mask in indoor settings. The concern, Lightfoot said, is that an increase in serious cases will overwhelm the city’s hospitals.
"We will protect the health care system from being overwhelmed," said Lightfoot, who wore a mask after announcing last week that she was infected with COVID-19 for the second time this year.
Lightfoot said that over the past week she barely felt symptoms of COVID-19, a contrast from January, and she credited that to receiving the latest booster shot available.
"If you haven’t had the COVID-19 vaccine since Labor Day, you’re not up to date," Lightfoot said.
The mayor also said it's a good idea to get the flu shot as well.
In September, the new booster that targets the pervasive Omicron strains of the virus was made available.
Only about one in five adult Chicagoans has received the latest booster, said Chicago Public Health Commissioner Allison Arwady, who also spoke at the news conference.
About 71% of Chicagoans have completed a first round of shots and only about 41% have received any type of booster, according to the city’s most current COVID-19 data.
Unvaccinated people are three times more likely to be hospitalized from COVID-19 than those who received a vaccine, Arwady said.
"That’s huge," she said. "You can cut your risk of ending up in the hospital."
The risk of death and hospitalization is down significantly from a year ago when the city was seeing a surge from Omicron.
The death rate is less than one a day on average, Arwady said, but continues to be the leading cause of death for Chicagoans.
As of Thursday, the city has recorded 7,968 deaths from COVID since 2020.
With the holidays approaching, Arwady said she expects an uptick in cases.
She encouraged Chicagoans to take a COVID-19 test before family gatherings and to stay home if experiencing any symptoms.
Sun-Times Media Wire contributed to this report.