Lightfoot had 74 percent of the vote with 94 percent of the precincts reporting and gave her victory speech just after 9 p.m.
"You did more than make history," Lightfoot said to supporters at the Grand Ballroom at the Hilton Hotel in the South Loop.. "You created a movement for change."
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She will be sworn in May 20, succeeding Mayor Rahm Emanuel, who opted not to run for a third term.
READ: Lori Lightfoot's prepared remarks
WATCH: Lori Lightfoot gives victory speech
Lightfoot will win all 50 wards, according to election data examined by the I-Team, some by huge margins of as much as 6-1.
Lightfoot has made history, defeating Toni Preckwinkle, the president of the Cook County Board and former history teacher and alderman.
In her concession speech, Preckwinkle said: "At the end of the day, that's what truly historic about this election, it's not simply gender or race but about our values. This campaign was about real issues. This was a campaign where support."
WATCH: Toni Preckwinkle's concession speech
During her campaign, the former federal prosecutor touted that she would bring change and end corruption.
Lightfoot, 56, who is a political newcomer and openly gay, was the top vote-getter in the February election when she defeated more than a dozen other candidates.
Chicago Mayoral Election 2019: Coverage of mayor's race, candidates and more
Polls closed at 7 p.m., but early numbers show low turnout, with more older voters casting their ballot. Bigger turnout was reported in precincts that Lightfoot had won in the primary election.
No major reports of polling issues were reported at poll sites.
The Associated Press also projected that Melissa Conyears-Ervin would win the Chicago treasurer seat.
WATCH: Son of aldermanic candidate attacked outside polling site
FINAL PUSH FOR VOTES
Both candidates spent the day making their last-minute appeal to voters.
Lightfoot was out meeting and shaking hands with voters outside a polling place in the 35th Ward where she lives.
"What we have heard from people is that they are really, really sick and tired of the same old, same old and want to break away from the past and I think that they view me as a change candidate, so I'm excited about that," Lightfoot said.
WATCH: Lightfoot addresses media after greeting voters early Tuesday
"This has been the most wondrous journey of my life. There's no question about it. You try to plot the course," Lightfoot said as she greeted voters in the 14th Ward Tuesday afternoon.
Preckwinkle was also out early, meeting commuters at the 95th Street Red Line station. The polls suggest she was trailing Lightfoot significantly heading into Election Day.
WATCH: Preckwinkle addresses media after voting
As Preckwinkle cast her own ballot, she was counting on a strong ground game of union support to help get her supporters to the polls. She is hoping people will find her message about her political experience one that resonates enough to propel her to victory.
"I'm really optimistic," Preckwinkle said. "I've had a great several weeks here and I'm encouraged."
She also spoke about what city issues she would want to tackle first, if elected mayor.
"I think we have to address the violence that plagues so many of our neighborhoods. But the response can't be solely a police response," Preckwinkle said after she voted Tuesday morning.
"What we've found in the county is that we need to support the anti-violence, anti-recidivism, restorative justice work that's done by so many so many community-based organizations and the organizations that support returning citizens. So if you're going to try to challenge the violence and crime, you have to have everybody at the table. It can't just be a police response. It's got to be a community-based response," Preckwinkle said.
Chicago Mayoral Election 2019: Who's in the race for mayor? Meet the Candidates
The election is special for many voters.
"It's interesting to see two candidates of this race and color and different viewpoints," said voter Dennis Nowacyk.
"I was actually wavering between the two, so a couple of friends helped make my final decision," said voter Denail Tims. "Either way I am happy it's a historic election.""