After graduating from Bishop Walsh School in Cumberland, Maryland, Perlozzo was drafted by the Twins after playing college ball at George Washington University.

On October 12, the "interim" title was dropped as Perlozzo was named the team's manager.

In 2006, Perlozzo's first full season as manager of the Orioles, the team finished with a 70–92 record.

Orioles owner Peter Angelos fired Perlozzo as the team's manager on June 18, 2007.

On November 5, 2007, the Seattle Mariners announced that Perlozzo had been hired as their third base coach.