Because the $85 billion in cuts are spread among domestic and defense budgets and don't differentiate about what is affected, Napolitano said, they make it difficult to mitigate security threats.
"We're going to do everything we can to minimize that risk, but the sequester makes it awfully, awfully tough," she said.
"Put simply, the automatic budget reduction mandated by sequestration would be disruptive and destructive to our nation's security and economy," the secretary said during a White House media briefing. "It would negatively affect the mission readiness and capabilities of the men and women on our front lines. It would undermine the significant progress we've made over the past 10 years to build the nation's preparedness and resiliency."
She said the department has begun to furlough Customs and Border Protection officers at ports of entry. The average wait time to customs will increase by as much as 50 percent, she estimated, and at the busiest airports peak wait times "could easily grow to four hours or more."
"I don't think we can maintain the same level of security at all places around the country with sequester compared to without sequester," said Napolitano, whose agency includes the Transportation Security Administration.
Transportation Secretary Ray LaHood said Friday air travelers could expect longer waits because of the cuts and Sunday the Obama administration released a scorecard of how the sequester would affect each state in education.
The cuts will also affect the departments of Defense and Justice, as well as other national security spending.
"I think if you look at the combination of the effect on [the Department of Homeland Security], the Department of Justice and the Department of Defense, we are having real impacts on the robustness of our defensive posture," Napolitano said.
Napolitano said the cuts would reduce Coast Guard patrols by 25 percent and decrease the number of beds for immigration detentions.
"When you slow down the inspection of [cargo ship] containers by up to five days ... that translates into lots and lots of jobs, good paying jobs, and those are going to be impacted," Napolitano said.
It also would reduce the department's investigative activities and areas such as human smuggling and commercial trade fraud, she said.
Concerning the nation's disaster preparedness, response and recovery efforts, "it will reduce the disaster relief fund by nearly $1 billion, potentially affecting survivors recovering from Hurricane Sandy, the tornadoes in places like Tuscaloosa [Ala.] a and Joplin [Mo.], and other major disasters across the country," Napolitano said.
"Threats from terrorism and the need to respond and recover from natural disasters do not diminish because of budget cuts," she said. "[We] do not have the luxury of making significant reductions to our capabilities without significant impacts. We will work to continue to preserve our frontline priorities as best we can, but no amount of planning can mitigate the negative effects of sequestration."