Mazzilli, 48, replaces Mike Hargrove who was fired following the season after going 71-91.
Baltimore's vice president of baseball operations Mike Flanagan and vice president Jim Beattie interviewed him last week.
"This is something I've wanted for a very long time," Mazzilli said at the time to the Associated Press. "You put your apprenticeship in, you pay your dues. Now is the time to do it."
In a fourteen year playing career, Mazzilli hit .259 with 93 homers and 460 RBI during time with the Mets, Rangers, Yankees, Pirates, and Blue Jays.
He now attempts to turn around an Oriole team that has finished in fourth place the last four seasons in a row.