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6 year oldA 15-year-old girl died at the scene at Marshall County High School in the town of Benton and a 15-year-old boy died in hospital, said Kentucky's governor.
The attacker, a 15-year-old male student, was arrested in "a non-violent apprehension", officials said.
State police said the unidentified boy was held about 15 minutes after opening fire at 08:00 local time on Tuesday.
The lone attacker opened fire with a handgun apparently at random in a common area before classes started, according to local media.
He will be charged with murder and attempted murder, said officials. The FBI was assisting in the investigation.
Police named the two students who died as Bailey Holt, pronounced dead at the school, and Preston Cope, who succumbed to his injuries in hospital.
Fourteen students were hit by gunfire, including the two who died.
Another five students suffered non-gunshot injuries while trying to escape the gunfire.
Jason Hall, a student at the school of nearly 1,150, described the stampede for the exits.
"I saw people getting shoved down," he said. "There was a lot of blood everywhere. It was horrible."
The attack shocked the small farming town of 4,500 people, situated about 130 miles (210km) north-west of Nashville, Tennessee.
"To walk in, the backpacks laying around, the phones laying around, going off, it's indescribable," Marshall County Attorney Jeffery Edwards told reports the Louisville Courier-Journal.
"I've been doing this for 25 years. It's not like anything I've experienced in my life."
Governor Matt Bevin called the attack a "tremendous tragedy" in a statement posted on Twitter.
"It is unbelievable that this would happen in a small, close-knit community like Marshall County," he said.
"As there is still much unknown, I encourage people to love on each other at this time.
"Do not speculate, but come alongside each other in support and allow the facts to come out."
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