A spokesman for U.S. House Speaker John Boehner's office confirmed Jackson, who has been hospitalized twice for bipolar disorder, had submitted his letter of resignation from the House.
"We have received the (resignation) letter," a spokesman in Boehner's office told The Washington Post.
"During this journey, I have made my share of mistakes," Jackson wrote in his letter. "I am aware of the ongoing federal investigation into my activities, and I am doing my best to address the situation responsibly, cooperate with the investigators, and accept responsibility for my mistakes, for they are my mistakes and mine alone. None of us is immune from our share of shortcomings or human frailties and I pray that I will be remembered for what I did right."
Jackson, 47, has been on medical leave from Congress since June and has been receiving treatment at the Mayo Clinic in Minnesota. After he left the clinic for the second time recently, media reports indicated a federal investigation of alleged misuse of campaign funds to pay for personal items had included his wife, Chicago Alderman Sandi Jackson, who reportedly receives $2,000 a month as a political consultant.
CLTV, a local cable news service, reported Jackson's father, civil rights activist Jesse Jackson Sr. said: "It has been a tough day," when asked to comment on his son's condition.
Jackson was reported in plea negotiations with federal prosecutors. The Chicago Sun-Times said Jackson hired attorney Dan Webb, a former federal prosecutor who is a noted criminal lawyer.
"For 17 years I have given 100 percent of my time, energy and life to public service," Jackson wrote. "However, over the past several months, as my health has deteriorated, my ability to serve the constituents of my district has continued to diminish.
"Against the recommendations of my doctors, I had hoped and tried to return to Washington and continue working on the issues that matter most to the people of the 2nd District. I know now that will not be possible.
"The constituents of the 2nd District deserve a full-time legislator in Washington, something I cannot be for the foreseeable future. My health issues and treatment regimen have been incompatible with service in the House of Representatives. Therefore, it is with great regret that I hereby resign as a member of the United States House of Representatives, effective today, in order to focus on restoring my health."
The resignation is the second in the heavily Democratic 2nd Congressional District. His predecessor, Mel Reynolds, was convicted of engaging in sex with a minor and other charges. Jackson won a special election to Congress in 1995 to replace Reynolds.
Illinois Gov. Pat Quinn has five days to announce the timing of a special election to fill Jackson's vacant seat, the Chicago Tribune said.