Former Thor writer Kieron Gillen returns to the character for the relaunch alongside artist Doug Braithwaite, while current writer Matt Fraction embarks on a new ongoing series called The Mighty Thor.
Gillen's project will focus on Thor's half-brother Loki, along with a host of supporting characters who will rotate between story arcs.
"If The Mighty Thor is Avengers, then Journey Into Mystery is Secret Avengers," Gillen explained to the publisher's official site. "The Mighty Thor storms the gates of Hell, Journey Into Mystery sneaks in the back door and ends the threat with a single strike.
"It's a mythological black ops comic, with a rotating team organised by the most Machiavellian figure in the whole Norse pantheon."
Loki recently underwent a number of changes when he was resurrected as a young boy. Gillen promised that the secrets behind his return will be revealed in the series' opening story arc.
Other characters confirmed to be appearing over the course of the next year include Tyr, Hela, Mephisto and Beta-Ray Bill.
Journey Into Mystery #622 will be published in April.