"We are aware of over 100 U.S. citizens who have U.S. passports who are fighting in the Middle East with [ISIS] forces. There may be more, we don't know," Hagel told CNN in an interview.
Authorities have been concerned that Americans and citizens of other Western nations could potentially return and launch terror attacks in their home countries.
A British citizen is believed to be the one shown on a video depicting the beheading of U.S. journalist James Foley, and intelligence agencies are investigating if the alleged executioner of Steven Sotloff, another U.S. journalist whose death was confirmed Wednesday, is the same person, according to reports.
At least two have been known to have been killed.
The latest, Abdirahmaan Muhumed of Minneapolis, formerly worked cleaning airliners at Minneapolis-St. Paul International Airport, where he held a security clearance that gave him widespread access, KMSP reported.
Muhumed was killed in the same battle in Syria as Douglas McAuthur McCain, who grew up in Minneapolis but later lived in San Diego.