At least four fellow students were critically injured in the assault at Franklin Regional High School, said Thomas Seefeld, chief of police in Murrysville, an outer suburb of Pittsburgh.
The 16-year-old boy walked down a hallway wielding two knives up to 25 centimeters long, stabbing fellow pupils and the guard as they began arriving for the school day, police said.
Panicked students rushed for the exit and one reportedly set off the fire alarm, but 20 pupils and one male security guard were injured, mostly in the chest and stomach, officials confirmed.
The school principal and another member of staff overpowered the suspect, who was arrested within five minutes of police officers being alerted by radio, police said.
The motive of the attack was not immediately clear.
One student described the suspect as "shy" and told CNN that he was "very quiet" while carrying out the assault.
"He just was kind of doing it and he had this look on his face that he was just crazy and he was just running around just stabbing everyone who was in his way," she told CNN.
She spoke of seeing at least two students gushing blood, one from his chest and a girl from the arm.
"I started hearing like a stampede of students coming down from the other end of the hall screaming, 'Get out, we need to leave, go, there is a kid with a knife,'" she said.
The assailant, who sustained an injury to his hand, has not been named although Westmoreland County District Attorney John Peck said he would in all likelihood be charged as an adult.
FBI and state police have been drafted in to assist with what is now expected to be a lengthy investigation.
Peck outlined the possible charges as aggravated assault and, in cases of serious injury, possible criminal attempt to commit homicide.
Doctor Mark Rubino at Forbes Regional Hospital, which is treating eight of the victims, said he expected everyone to survive, despite what he called "deep penetrating" stab wounds.
The knife wounds caused significant injuries to internal organs, Rubino said.
"Three of the patients had severe injuries and are still in the operating room right now. And two of them are in critical condition, but they have stabilized," Rubino said.
"The other five that we had are still being evaluated, of whom one or two may require further surgery."
Dan Stevens, a spokesperson for Westmoreland County emergency management, told AFP that the teenage victims were aged 14 to 17.
The incident lasted from 7:13 am to 7:45 am, he said.
They were attacked in "numerous classrooms and hallways" of the school, Stevens added.
Wednesday's attack comes after a long and frequent line of US school shootings that have inflamed a nationwide debate over gun control in the United States.
But even the December 2012 massacre at Sandy Hook Elementary in Newtown, Connecticut, where 20 young children and six adults were shot dead, ultimately failed to tighten gun ownership rules.
The police chief Seefeld praised school staff, who worked in close coordination with police and who were well versed in emergency procedure.
"It is my opinion that today, as unfortunate as it is... I think that it could have been a lot worse if there was not immediate interaction that occurred," he told reporters.
Franklin Regional High will be closed for several days.
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Let us also ban the knives!