On September 1, 2001, Fitzgerald was nominated for the position of U.S. Attorney for the Northern District of Illinois on the recommendation of U.S. Senator Peter Fitzgerald (no relation), a Republican from Illinois.
On October 24, 2001, the nomination was confirmed by the Senate.
The Senator urged the selection because Patrick Fitzgerald is not from Chicago; Patrick said that he had visited Chicago only one day, for a wedding in 1982, before his selection.

Soon after becoming U.S. Attorney for Northern Illinois, Fitzgerald began an investigation of political appointees of Republican Illinois Governor George Ryan, who were suspected of accepting bribes to give licenses to unqualified truck drivers.
Fitzgerald soon expanded this investigation, uncovering a network of political bribery and gift-giving, and leading to more than 60 indictments.
Ryan was indicted in December 2003.
At the conclusion of the trial in April 2006, Ryan was found guilty on all eighteen counts against him.
Ryan's co-defendant, Chicago businessman Larry Warner, then 67 years old, was convicted of racketeering conspiracy, fraud, attempted extortion, and money laundering.
The two were sentenced on September 6, 2006: Ryan received a sentence of six and one half years, and Warner received a sentence of three years and five months.

Against criticism that these cases were based on circumstantial evidence, Fitzgerald responded: "People now know that if you're part of a corrupt conduct, where one hand is taking care of the other and contracts are going to people, you don't have to say the word 'bribe' out loud.
And I think people need to understand we won't be afraid to take strong circumstantial cases into court."

On July 18, 2005, his office indicted a number of top aides to Democrat Richard M. Daley, the mayor of Chicago, on charges of mail fraud, alleging numerous instances of corruption in hiring practices at City Hall.

In March 2006, former Chicago City Clerk James Laski pleaded guilty to pocketing nearly $50,000 in bribes for steering city business to two trucking companies.
Laski was the highest-ranking Chicago official and Daley administration employee brought down by Fitzgerald's office in conjunction with the Hired Truck Program scandal.
Beginning in April 2007, Fitzgerald oversaw Operation Crooked Code, the investigation and prosecution of over two dozen defendants for bribery and related charges in City of Chicago's Departments of Buildings and Zoning.

On December 9, 2008, federal agents arrested Governor Blagojevich for conspiring to profit from his authority to appoint President Barack Obama's successor to the U.S. Senate.
Fitzgerald said Blagojevich "put a 'for sale' sign on the naming of a United States Senator."

United States Senator Peter Fitzgerald chose not to run for reelection in 2004, leaving Patrick Fitzgerald without a congressional patron.
In the summer of 2005, there were rumors that he would not be reappointed to a second four-year term in retaliation for his investigations into corruption in Illinois and Chicago government, as well as for his investigation of the Plame scandal.
On May 23, 2012, Fitzgerald held a press conference informing the public that he was stepping down from his position and retiring as the US Attorney for the Northern District of Illinois Federal Court effective June 30, 2012.
Long-time prosecutor Gary S. Shapiro was named US Attorney until a replacement had been selected.

In 2013, Fitzgerald was appointed by Governor Patrick Quinn (D-IL) to the Board of Trustees for the University of Illinois.
On September 1, 2001, Fitzgerald was nominated for the position of U.S. Attorney for the Northern District of Illinois on the recommendation of U.S. Senator Peter Fitzgerald (no relation), a Republican from Illinois. On October 24, 2001, the nomination was confirmed by the Senate. The Senator urged the selection because Patrick Fitzgerald is not from Chicago; Patrick said that he had visited Chicago only one day, for a wedding in 1982, before his selection.
Soon after becoming U.S. Attorney for Northern Illinois, Fitzgerald began an investigation of political appointees of Republican Illinois Governor George Ryan, who were suspected of accepting bribes to give licenses to unqualified truck drivers. Fitzgerald soon expanded this investigation, uncovering a network of political bribery and gift-giving, and leading to more than 60 indictments. Ryan was indicted in December 2003. At the conclusion of the trial in April 2006, Ryan was found guilty on all eighteen counts against him. Ryan's co-defendant, Chicago businessman Larry Warner, then 67 years old, was convicted of racketeering conspiracy, fraud, attempted extortion, and money laundering. The two were sentenced on September 6, 2006: Ryan received a sentence of six and one half years, and Warner received a sentence of three years and five months.
Against criticism that these cases were based on circumstantial evidence, Fitzgerald responded: "People now know that if you're part of a corrupt conduct, where one hand is taking care of the other and contracts are going to people, you don't have to say the word 'bribe' out loud. And I think people need to understand we won't be afraid to take strong circumstantial cases into court."
On July 18, 2005, his office indicted a number of top aides to Democrat Richard M. Daley, the mayor of Chicago, on charges of mail fraud, alleging numerous instances of corruption in hiring practices at City Hall.
In March 2006, former Chicago City Clerk James Laski pleaded guilty to pocketing nearly $50,000 in bribes for steering city business to two trucking companies. Laski was the highest-ranking Chicago official and Daley administration employee brought down by Fitzgerald's office in conjunction with the Hired Truck Program scandal. Beginning in April 2007, Fitzgerald oversaw Operation Crooked Code, the investigation and prosecution of over two dozen defendants for bribery and related charges in City of Chicago's Departments of Buildings and Zoning.
On December 9, 2008, federal agents arrested Governor Blagojevich for conspiring to profit from his authority to appoint President Barack Obama's successor to the U.S. Senate. Fitzgerald said Blagojevich "put a 'for sale' sign on the naming of a United States Senator."
United States Senator Peter Fitzgerald chose not to run for reelection in 2004, leaving Patrick Fitzgerald without a congressional patron. In the summer of 2005, there were rumors that he would not be reappointed to a second four-year term in retaliation for his investigations into corruption in Illinois and Chicago government, as well as for his investigation of the Plame scandal. On May 23, 2012, Fitzgerald held a press conference informing the public that he was stepping down from his position and retiring as the US Attorney for the Northern District of Illinois Federal Court effective June 30, 2012. Long-time prosecutor Gary S. Shapiro was named US Attorney until a replacement had been selected.
In 2013, Fitzgerald was appointed by Governor Patrick Quinn (D-IL) to the Board of Trustees for the University of Illinois.
Patrick Fitzgerald