McDonough, a longtime Obama foreign policy adviser who worked on the 2008 campaign, would bring a strong working relationship and long history with the president to the job.
Two associates of McDonough told Reuters they would be surprised if he did not land the position, though administration officials have indicated it is not a done deal.
An announcement is expected soon.
McDonough, a foreign policy expert, would have a broad domestic portfolio as chief of staff. President Barack Obama has identified deficit reduction, immigration reform and gun control as his top policy priorities for the first year of his second term.
Rob Nabors, the White House director of legislative affairs who was a critical player in the "fiscal cliff" talks with congressional leaders, is expected to be promoted to deputy chief of staff, according to one source with close ties to the White House. Nabors would replace Nancy-Anne DeParle.
McDonough has been on the White House National Security Council since Obama became president, with stints as National Security Council chief of staff and communications chief before assuming his current role of assistant to the president and deputy national security adviser.
As part of the senior foreign policy team, McDonough has helped shape the administration’s response to Iran's nuclear ambitions, the uprisings in Arab nations and the winding down of the Iraq and Afghanistan wars, The Wall Street Journal notes.
"Denis is the perfect choice for the second term for two important reasons," former Senate Majority Leader Tom Daschle, D-S.D., who once employed him in his Senate office, told the Journal. "First, I doubt that there is anyone the president trusts more. Second, as a result, he comes to the position with enormous authority and credibility. That will serve him very well as he works with Congress, the Cabinet and virtually everyone else."