The pair are to collaborate on comedy The Beaver, which recounts the tale of a depressed man who finds solace in his beaver hand-puppet. Mel's last major big screen role was 2003's The Singing Detective.
Dad of seven Mel - who is expecting his first child with new girlfriend Oksana Grigorieva – has already worked with Jodie in 1994 comedy Maverick.
The Silence Of The Lambs star has previously directed 1991 drama Little Man Tate and romantic comedy Home For The Holidays in 1995.
Producers of The Beaver hope to begin shooting in New York this September. The script for the quirky movie has previously attracted the attention of a number of Tinseltown names, including Jim Carrey and Steve Carell.