The Doctor Who actor will play George Milton, while Liam Brennan is cast as Lennie Small. It will be produced by BBC Radio Scotland and is scheduled to air on Radio 4 in early 2010.
Steinbeck's classic novel about two migrants in 1930s California has been adapted on several occasions with Burgess Meridith, Lon Chaney Jr, George Segal, John Malkovich and Nicol Williamson among the stars to take on the lead roles.
Tennant departs Doctor Who at the end of the year after three special episodes. His other upcoming projects include a BBC Two adaptation of his recent stage performances in Hamlet with the Royal Shakespeare Company.