Lupo was born in South Carolina but grew up in Decatur. He moved to Birmingham to attend Samford University. Lupo spent more than 28 years in the men's clothing business. In the 1990s he was president of the Redmont Park neighborhood association.
In 1999, Lupo was appointed director of MOCA after Bernard Kincaid took office as Mayor of Birmingham. In 2007, after Kincaid was defeated by Larry Langford, Lupo was retained as co-director of MOCA, along with Langford ally and radio talk-show host Frank Matthews, which lasted until 2009 when Langford was removed from office after a bribery conviction. Subsequent mayors Roderick Royal and William Bell retained Lupo.
- Bryant, Joseph D. (November 17, 2007) "Birmingham Mayor Larry Langford retains more department heads from Bernard Kincaid's administration." The Birmingham News
- Gray, Jeremy (January 21, 2016) "Don Lupo is Birmingham's modern day Brother Bryan." The Birmingham News
- MOCA at InformationBirmingham