The Air Evac Lifeteam helicopter went down near the Scotland community in Van Buren County at about 4:30 a.m., Federal Aviation Administration spokesman Lynn Lunsford said.
"They were flying under (visual flight rules)," Lunsford said. "It doesn't appear they were talking to any air traffic controllers at the time."
No patients were aboard the Bell 206 aircraft.
The helicopter, built in 1978, was registered to Air Evac EMS Inc., based in West Plains, Mo.
Air Evac spokeswoman Julie Heavrin said the immediate family members of the crew had been notified and that the names would be released later, after friends and other family could be told of the deaths.
Air Evac Lifeteam President and CEO Seth Myers said in a news release that the helicopter was equipped with night vision gear.
"This is a tragic day for us here at Air Evac Lifeteam," Myers said. "These were members of our family and we are devastated at this loss. Our focus at this time is on providing support for the family and friends of these crew members."
Investigators from the FAA and the National Transportation Safety Board were traveling to the crash site, Lunsford said, who is based in the FAA's regional office in Fort Worth, Texas.
Lunsford said there apparently was no distress call.
Scotland is about 80 miles north of Little Rock in central Arkansas.
Air Evac has experienced several fatal crashes in recent years, the latest in March when three crew members were killed in western Tennessee.
In 2008, an Air Evac helicopter crashed in an Indiana cornfield killing three people. In 2007, another three-member crew was killed when an Air Evac helicopter crashed in Colbert County, Ala.
The company operates in 13 states.