The shots were reportedly fired inside a classroom at Sal Castro Middle School, Los Angeles.
A male and female student, both aged 15, suffered gunshot wounds.
Cops say the boy is in a critical condition after suffering a gunshot wound to the head, with the girl in a stable condition.
The girl was reportedly shot in the wrist, and the weapon used is now in custody.
Two others were grazed by bullets, according to reports.
KTLA
A 30-year-old woman and two others have suffered minor injuries, but not gunshot wounds.
Police said a suspect, a teenaged girl, 12, has been arrested and is in custody.
She has been seen being taken away by police.
Earlier, LAPD said: "Sal Castro Middle School on lock down, police are conducting a search of the school.
"One suspect in custody, there are no outstanding suspects. LAPD PIO at scene at media staging 3rd St & Loma."
In follows a string of shooting that rocked the US last year.
In October last year, Stephen Paddock massacred 58 from the Mandalay Bay hotel, Las Vegas, before shooting himself dead.