Authorities say seven adults are hospitalised, including three with critical injuries.
The explosion, which happened during construction work on the gas supply, ripped Minnehaha Academy's Upper School in half about 10am. It destroyed the main stairwell and a group of classrooms for Years 9-12.
According to the Daily Mail, a small number of children were in the gym and on the field at the time of the explosion, but authorities said the students were not harmed. All of those reported missing or injured are adults, they said.
Emergency personnel move away as a gas fire continues to burn following an explosion at Minnehaha Academy in Minneapolis. Photo / AP
Those on school property at the time of the explosion included staff and student basketball and soccer players and the girls' cross-country team.
School officials said all of the students - some of whom were on the field at the time, and many of whom were in the gym - had been accounted for.
Previously, two people were missing, according to assistant fire chief Brian Tyner. He said that rubble is being combed for the pair but they could also be "walking around out here".
"I'm not confident that they are in there," he told the Star Tribune. "Our hopes are that they are not in there."
The unaccounted-for figure was originally three, but one of the people was found unharmed outside the building.
Nine people were hospitalised at Hennepin County Medical Centre (HCMC) after the explosion, three in critical condition and one was treated and released.
Four victims were said to be in serious condition, and two had "very minor trauma" according to HCMC chief of emergency services, Dr Jim Miner.
They suffered fractures, cuts and bruises, not burns, and that "It could have been a lot worse", he said. "We were relieved, we were prepared for a lot more injuries. It was a terrible tragedy."
Emergency workers respond to an explosion at Minnehaha Academy in Minneapolis. Photo / AP
No details are available about the other victims, other than they were not in critical condition.
Firefighters rescued three school employees from the roof of the building, a father visiting the school at the time of the explosion said. It's not clear why they were on the roof.
It's believed that the gas leak may have been caused by a ruptured gas line. Part of the brick building collapsed after the explosion, authorities said.
CenterPoint Energy spokeswoman Becca Virden said the gas supply to the school had been cut off after the explosion and that "well-trained, experienced crews on site [are] coordinating with local emergency officials to secure the area".
"We will conduct an investigation to determine the cause," she added.
City of Minneapolis records obtained by the Star Tribune said Master Mechanical Inc had a permit for "gas piping and hooking up meter" at the school.
The company had previously been fined US$1000 ($1350) in 2010 for a violation related to a worker's protection from falling and US$600 in 2014 for paperwork violations regarding hazard communication and an employee's right to know, paperwork said.
Minnesota OSHA spokeswoman Jenny O'Brien said neither were "huge penalties".
Former Minnehaha Academy employees Elizabeth Van Pilsum, left, and Rick Olson, center, react after an explosion at the school in Minneapolis. Photo / AP
The explosion only affected the upper school, officials said; the lower school is several miles away and is undamaged.
A school gym coach said that the explosion came seconds after an alarm was raised. He said someone had smelled gas.
A father in the school said two groups were inside the building when the explosion occurred: a group in the counsellors' office having a meeting, and about a dozen students in the gym, practising basketball.
He said his daughter went to the door when the alarm went off, but was blown back by the explosion. She was unharmed, he said.
The school's director of advancement, Sarah Jacobson, said staff and children were told to evacuate before the explosion, although she declined to give further details.
Sophomore student and cross-country runner Kylee Kassebaum was inside the building at the time of the explosion; she and the rest of her cross-country team were about to get an early lunch.
"All the windows just kind of burst out, and there was a huge explosion that was so loud it kind of shook your insides," she said.
"As soon as we saw it we got in the car, and someone drove away because we didn't know how safe the situation was."
Tom Haubrich, who graduated from the Academy in May, went to the scene after he heard the reports of the explosion, and said that if it had occurred during term-time hundreds would have been caught in the blast.
Flames shoot up as firefighters train water hoses on the scene of a collapsed building following an explosion at Minnehaha Academy in Minneapolis. Photo / AP
"That is where everybody would've been during the school year," he said. "That's the stairwell that connects the entire school to everything."
The school's campuses reopen on August 23.
Flames continued to burn an hour after the explosion, likely fed by gas lines, but were ultimately extinguished. Firefighters kept their hoses on the smouldering ruins to ensure the flames did not reignite.
"Being briefed regularly by Chief Fruetel and Acting Chief Arradondo regarding the gas explosion and building collapse at Minnehaha Academy," mayor Betsy Hodges tweeted shortly after news broke. "City first responders are fully engaged."
Those in the neighbourhood said the explosion rattled windows on nearby buildings. "It was just a really loud boom," one resident told KARE 11. "You felt it in your chest."
Minnesota Governor Mark Dayton said his office was in constant contact with the school.
Tuition fees at the Minnehaha Academy cost between $12,470 A year for kindergarteners and $21,280 for those in Grade 12.
It had 825 students enrolled during its 2015-16 year; one student said that had the explosion occurred during term-time, hundreds would have been caught in the blast.
Children can be picked up by their parents from Edmond Blvd and 32nd St, next to the school, according to Jacobson.