The suicide bomber struck an American convoy as it was moving through the provinical capitol of Qalat.
U.S. officials in Kabul confirmed one of the two civilians killed in the attack was a State Department official. As many as nine other Americans and Afghans were wounded in the attack.
In Eastern Afghanistan, a U.S. soldier was killed during combat operations against Taliban forces in the country.
"There are American and Afghan casualties. We are still investigating the incident and cannot confirm details at this time," according to a statement by the U.S. embassy in Afghanistan.
The attacks come on the same day as chairman of the Joint Chiefs of Staff, Gen. Martin Dempsey, arrived in Afghanistan to meet with U.S., NATO and Afghan leaders.
Dempsey’s visit is to assess the ongoing effort to end America's war in the country within the next year.
U.S. and NATO forces are in the midst of what will likely be the final fighting season for American troops before the White House's withdrawal deadline of 2014.
The 66,000 American troops still in Afghanistan are preparing to pull out of the country this spring. The final group of those U.S. forces is expected to leave the country next April.