It happened just before 2 p.m. at a home on James Jack Lane off Ballantyne Commons Parkway that is estimated to be worth more than $1.5 million.
The Charlotte Fire Department confirmed to WSOC the house collapsed due to a fire.
Firefighters said a man made several calls to 911 to say he was trapped in the home after the explosion.
That man was later identified as homeowner Dr. Jebran Karam, a cardiologist and CEO of Raleigh General Hospital in Beckley, West Virginia. He was rescued and airlifted to the hospital with life-threatening injuries.
The Charlotte Fire Department said in a news conference that they later recovered a second person in the rubble, but that person had died.
Authorities said they were able to locate the woman, 58-year-old Rania Karam, with the help of Karam.
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It is unclear what the relationship was between the two.
A neighbor said she felt her house shake at the time of the incident.
"It shook...like I shook and I said, 'oh!' and I walked for a second, and something just told me to turn around and walk back and I turned around and all of the neighbors just started running out of their houses," the neighbor said.
Officials said there are two patients being evaluated from surrounding homes for non-life-threatening injuries.
It's unknown how many people were inside the home.