The size of the series order is still being determined, with the network eyeing a fall debut.
"Treme" is a post-Katrina-themed drama that chronicles the rebuilding of New Orleans through the eyes of local musicians.
Simon co-created the project with longtime New Orleans resident Eric Overmyer, after the two former "Homicide" writers had discussed doing a show set in the Big Easy for years.
"New Orleans is one of the most unique and essential American places, which is also very vulnerable," Simon said.
The "Treme" cast is led by another New Orleans native, Wendell Pierce, and includes Steve Zahn, Clarke Peters, Khandi Alexander, Melissa Leo, Kim Dickens and Rob Brown.
Despite featuring "Wire" alums Pierce and Peters, people expecting the same show will be disappointed, Simon said.
"This is not a 'Wire' redo with a New Orleans soundtrack," he said. "It's more of a character study looking at people trying to reconstruct their lives after their city has been destroyed and at a city that a living, breathing organism."
The series will continue to be filmed in the Crescent City, where the pilot was shot.
Simon and Overmyer are exec producing with Nina K. Noble and Carolyn Strauss. David Mills is co-exec producing.
The order for "Treme" follows HBO's series pickups of three new comedies: Hung, "Bored to Death" and "How to Make It in America."
The network has one more strong possible contender on the drama side in the Martin Scorsese-directed pilot "Boardwalk Empire," which has not been completed.