Frenchman Der Zakarian, who also has Armenian citizenship, spent four years at Stade de la Mosson between 2017-2021, leading them to a sixth placed finish and the French Cup semi-finals.
He was also their assistant coach between 1998-2006 after finishing his playing career there.
"I hope he will bring all his desire that he brought during his first stint with the first team and will manage to keep the club in Ligue 1," Montpellier president Laurent Nicollin said.
"I hope and I think he is the man for the moment," he added.
Four out of the French top-flight's 20 teams will be relegated this season as the league is decreased to 18 clubs.
Only two teams will be promoted from Ligue 2.
The 59-year-old's first game in charge during his second spell of the side in 15th place in the table will be on Sunday against his former outfit in Brest, who are one place above them on goal difference.