The actor will reprise his original role of Lucas Scott after Bethany Joy Galeotti's character Haley contacts him for help, The CW has announced.
Murray revealed last month that he would "definitely" be open to returning to One Tree Hill.
The star confirmed his exit from the series in 2009, as Lucas was seen driving off into the sunset with his wife Peyton (Hilarie Burton) and their new baby Sawyer.
Production on One Tree Hill's upcoming season was shut down at the weekend due to Hurricane Irene.
One Tree Hill will return mid-season on The CW.
> 'One Tree Hill' casts hit man for final season