Calderon said the helicopter was flying in fog when it went down in a remote area southeast of Mexico City, but that all possible causes were under investigation.
"Mexico has lost a great patriot," said Calderon, visibly struggling to maintain composure during address to the country. "It was probably an accident."
Authorities said the undersecretary for human rights, Felipe Zamora, was among the seven others also killed.
Calderon appointed Blake Mora as interior secretary in July 2010. That put him in charge of coordinating domestic policies including security, human rights, migration and the president's relation with the legislature and opposition parties.
He also a key figure in directing Mexico's battle against drug cartels and organized crime.
His death, while a blow to the government, is not likely to change policy or day-to-day operations.
Blake was traveling to a prosecutors' meeting in the neighboring state of Morelos when the helicopter went down in a mountainous area of Mexico State.
Calderon lost an earlier interior secretary, Juan Camilo Mourino, in the crash of a Learjet in Mexico City on Nov. 4, 2008. Despite widespread speculation that the accident, which killed 14, was caused by sabotage, investigators eventually blamed pilot error.
One of Blake's last postings on his Twitter account commemorated the loss of Mourino.
"Today we remember Juan Camilo Mourino three years after his death, a person who was working to build a better Mexico," Blake tweeted on Nov. 4.
Blake Mora, 45, started his political career in the mid-1990s as an official in his native Tijuana and served as a federal congressman through the 2000s, as well as interior secretary of Baja California.
As Calderon's point man in the government's war against organized crime, he frequently traveling to the country's most dangerous places for meetings with besieged state and local security officials.
He was an embodiment of the Mexican government's get-tough attitude, publicly pledging to bring the fight to the traffickers instead of backing down.
"Organized crime, in its desperation, resorts to committing atrocities that we can't and shouldn't tolerate as a government and as a society," he said.
He also oversaw response to disasters, such as flooding and the massive oil pipeline explosion that laid waste to parts of the central city of San Martin Texmelucan last year, killing at least 28 people.
He led the creation of a new national identity card for youths under 18, with modern features including digitalized fingerprints and iris images, to prevent criminals from using false IDs.
It was hard for many to believe that two interior secretaries could die in air accidents in the same administration.
"This is very unfortunate," said Sinaloa Congressman Manuel Clouthier, whose own father, a popular politician in Calderon's National Action Party, died in a still-unexplained highway accident in 1989. "There are many coincidences because now we have two interior ministers (lost) in one presidential term ... who knows if we'll ever really know what happened."
