The death of the president of the world's No. 2 cocoa grower comes months before Mills was due to stand for re-election at the helm of the West African country that posted double-digit growth in 2011 and has been praised for its strong democracy in a turbulent region.
"It is with a heavy heart...that we announce the sudden and untimely death of the president of the Republic of Ghana," a statement sent to Reuters by the president's office said.
It said that Mills, 68, died a few hours after being taken ill but no further details were given.
A presidential aide, who asked not to be named, said the president had complained of pains on Monday evening and died early on Tuesday afternoon when his condition worsened.
Mills, who oversaw the start of oil production in Ghana, returned from medical checks in the United States several weeks ago.