Her comments came in an interview with WTTW, a local PBS station, to discuss the city's recent surge in violence and those criticizing her leadership efforts.
Lightfoot said that "about 99%" of her criticism is motivated by racism and sexism when asked how much of the negativity she faces is based on her gender and race.
"Look at my predecessors," she said. "…Women and people of color are always held to a different standard. I understand that. I've known that my whole life."
She added that she is "fighting for the residents" of Chicago.
Nearly 1,500 people have been shot so far in Chicago in 2021 – a 12% increase compared to 2020 and a 59% increase compared to 2019, according to the Chicago Police Department's crime statistics for the week ending June 27. Shootings were down in June, however, by 20%, compared to last year.
Over the weekend ending June 27, six people died and 74 were shot in a total of 46 shooting incidents.
Lightfoot blamed the violence on several factors, including the COVID-19 pandemic and gun laws in the states and locales surrounding Chicago.
"I believe that violence is a manifestation of systemic problems, and it's a public health crisis," she said in the interview. "When you see, in way too many neighborhoods, a lack of jobs, a lack of investment – these are historic, decades-long problems."
Chicago is "surrounded by" suburbs and states "that have very lax gun laws," Lightfoot continued.
"We know that federally licensed gun dealers are selling to criminals and straw purchasers," she said. "…We know that because of our proximity to states like Indiana, Wisconsin and Michigan that … you can go across the border into these states, and if you've got the cash, you can buy literally military-grade weapons of any quantity and bring them back to Chicago."
The mayor last month declared racism a public health crisis, pointing to systematic racism as a leading factor in life expectancy discrepancies across the city.
Joined by the Chicago Department of Public Health, Lightfoot said there is a 9.2-year life expectancy gap between Black and non-Black Chicagoans.
Lightfoot said the city would be implementing a "will to act" initiative that will focus on addressing the impacts of historical policies like Jim Crow restrictions, redlining and "other forms of financial and housing segregation and discrimination."
The city's public health department said it will allocate nearly $10 million in coronavirus relief funds from the Centers for Disease Control and Prevention (CDC) to establish six Healthy Chicago Equity Zones that will encompass the entire city.
Fox News' Caitlin McFall contributed to this report.