The airplane was carrying 58 people from New York to Seattle when it went missing in 1950. There were no survivors, marking it the worst aviation disaster in the U.S. at the time.
The Michigan Shipwreck Research Association has spent years searching for NWA Flight 2501, discovering 10 shipwrecks along the way.
Researchers plan to narrow the search area for NWA Flight 2501 and use more advanced equipment this spring.
The team launched its search Wednesday and hopes to begin expeditions early next month.
"I'm more hopeful than ever because now, we are (searching) in the most logical place for the plane to have crashed. It's only a matter of time," said Valerie van Heest, association president and an underwater explorer.
The association is working with Greg Busch, an oceanographer and owner of Busch Marine in Freeland. Busch has a specialized "sonar sled" and a submarine to scour the Great Lakes' deep waters.
"The two big unanswered questions are: Why did it crash and where did it crash?" Busch said. "We hope to answer both of those."
Some researchers have speculated from the limited debris found that the plane may have exploded midair or experienced the equivalent of an explosion when it hit the water.
Relatives and friends of NWA Flight 2501 passengers are still seeking answers decades later.
"It's a very important event in all of our lives," said Kenneth Skoug III, whose grandfather was on the missing plane. "We just want to know more about it."
Discovering NWA Flight 2501 will offer families closure and answers, said van Heest. "We wanted very badly to do this for them," she said.