The actor - best known for his role as Elliot Stabler on Law & Order: Special Victims Unit - will join the show for its fifth season.
True Blood showrunner Alan Ball had hinted last month that Meloni would play an ancient and powerful vampire with control over the fate of Bill and Eric. The news has now been confirmed by an HBO spokesperson.
Meloni spent 12 seasons playing NYPD detective Stabler on Law & Order: SVU and said upon his departure that he felt "very blessed" to have been a part of the show.
He also expressed regret at the end of his partnership with co-star Mariska Hargitay, saying: "You know, I don't know if there's been any other duo for 12 years on TV."
Meloni will also appear in Superman: Man of Steel, where he will be seen playing a general.
True Blood will return to HBO in summer 2012.