A three-count indictment says Seale trained a shotgun on the teenagers while his companions beat them. Then they attached heavy weights to the pair and threw them alive into the Mississippi River.
Seale faces a maximum life term on each count if convicted. A bail hearing in the case is expected on Monday.
Until Thursday no one had been charged with the murders of the two 19-year-olds, Henry Hezekiah Dee and Charles Eddie Moore, although they were long thought to have been abducted and killed by members of the Klan.
According to the indictment, "on or about May 2, 1964, defendant Seale aimed a sawed-off shotgun at Dee and Moore" while fellow members of the White Knights of the Ku Klux Klan "beat them with switches and tree branches".
It said Seale and the others attached an engine block to Dee, took him on to the Mississippi in a boat and threw him in. They attached iron weights and railway rails to Moore and also threw him into the river, the indictment said.
The murders attracted little publicity at the time and were typical of dozens in the country's "Deep South". Many incidents involved Klan members protected by local authorities who approved of their efforts to tyrannise blacks and halt the civil-rights movement.
The movement, led by Martin Luther King, used non-violent tactics and civil disobedience in a campaign to outlaw racial segregation in the south and permit blacks to vote there.
Alberto Gonzales, the US attorney-general, said: "These allegations are a painful reminder of a terrible time in our country ... when some people viewed their fellow Americans as inferior and as a threat based only on the colour of their skin."
Dee and Moore were killed on the pretext that whites feared that activists from the Student Non-violent Co-ordinating Committee were running guns into the area, according to the Clarion-Ledger newspaper in Mississippi.
Their bodies were recovered during a search for three other civil rights activists later that year.
In 2005, a jury in Mississippi convicted Edgar Ray Killen, a Klan member, of manslaughter over those killings. The case led to revulsion at opposition to civil rights in the 1960s, in part because two of the victims were white volunteers from New York working to register blacks to vote during a "Freedom Summer" campaign.