More then seven gunmen wearing military uniform attacked the home of Warren and Donna Petts, both of whom worked for the African Inland Mission (Aim), in Eyeke village in Yumbe district late on Thursday killing them and a Ugandan, Isaac Jurugo, police spokesperson Asuman Mugenyi said.
The victims were working in an agriculture training institute run by the mission's Here is Life project in the area.
"Last evening, the technical school was attacked by an armed group," Aim deputy executive officer, William Stough, told reporters in Kampala.
"Buildings were burnt and other properties destroyed and an American missionary couple serving Aim mission, Warren and Donna Petts, were shot and killed. One student was also killed while another was wounded," he added.
He said the US couple came from Wisconsin and had lived in Uganda for almost a year.
The raiders also burned down 12 thatched houses near the Petts's compound.
"We don't know whether they were thugs or rebels, but investigations are still going on," said Mugenyi of the killers.
Aim also runs a radio station known as Voice of Life in Arua town.
The motive for the attack has not been established, Resident District Commissioner, Drani Dradiga, said. The raiders also robbed some staff and students of the college of money, he added.