The 49-year-old actor will feature in as twin brothers Dominick and Thomas Birdsey in "I Know This Much Is True", reported Deadline.
The show will be directed by Derek Cianfrance of "The Place Beyond the Pines" fame.
The script has been adapted from the popular 1998 novel by Wally Lamb, which will follow the brothers wade through the latter stages of the 20th-century in what is described as "a heartbreaking and poignant multigenerational saga of the reproductive bonds of destruction and the powerful force of forgiveness."
This marks Ruffalo's return to HBO where he starred in and co-executive produced the movie "The Normal Heart", which earned him an acting Emmy nomination.