U.S. officials say coalition and Afghan forces engaged a handful of "extremists" in a remote part of Kandahar province late Saturday night.
Military spokeswoman Lieutenant Tamara Lawrence says the militants initially opened fire from a ridgeline before fleeing to a compound where dozens more insurgents joined the fight.
"Afghan and coalition forces pressed the attack with joint fires and a ground assault, killing an estimated 45 extremists," Lawrence says.
Two coalition soldiers were also killed in the fight and a third was injured.
More than 10,000 Afghan and coalition troops are mounting a massive offensive throughout southern Afghanistan.
The military push follows a sharp rise in insurgent activity but U.S. officials say the new operation is reclaiming vast portions of the troubled region.
Coalition forces have killed more than 100 militants in the past two days in scattered clashes.