Napolitano released a statement confirming a report first made public in the Los Angeles Times:
"After four plus years of focusing on these (homeland security) challenges, I will be nominated as the next President of the University of California to play a role in educating our nation's next generation of leaders," Napolitano said.
Her departure comes as President Barack Obama tries to move a massive immigration overhaul with a divided Congress struggling to find common ground on how to deal with the estimated 11 million people who are in the country illegally.
Napolitano will be the first woman to head the 10-campus system. The former Arizona governor, a graduate of Santa Clara University and the University of Virginia Law School, has previously been mentioned as a potential Supreme Court nominee.
"The opportunity to work with the dedicated men and women of the Department of Homeland Security, who serve on the frontlines of our nation's efforts to protect our communities and families from harm, has been the highlight of my professional career," Napolitano said.
"We have worked together to minimize threats of all kinds to the American public. The Department has improved the safety of travelers; implemented smart steps that make our immigration system more fair and focused while deploying record resources to protect our nation's borders; worked with states to build resiliency and make our nation's emergency and disaster response capabilities more robust; and partnered with the private sector to improve our cybersecurity."
"While some may consider her to be an unconventional choice, Secretary Napolitano is without a doubt the right person at the right time to lead this incredible university. She will bring fresh eyes and a new sensibility - not only to UC, but to all of California," said Sherry Lansing, a University of California regent.
A former movie executive, and chair of the university's presidential selection committee, Lansing added that Napolitano "rose to the top" among some 300 potential candidates considered.
"Janet Napolitano will make a fine president of the University of California. I welcome her to California and look forward to a new constituent," said Democratic Sen. Dianne Feinstein, whose husband, Richard Blum, has served as a UC regent.
PHOTO: Janet Napolitano, director of the Department of Homeland Security, shown on April 17, 2013, announced on July 12, 2013, that she will resign. Abaca Press/Olivier Douliery